Antibacterial Cannabinoids from Cannabis sativa: A Structure-Activity Study

ArticleinJournal of Natural Products 71(8):1427-1430 · September 2008with 4,814 Reads 
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Abstract
Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.

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  • ... Benzochromenes are polycyclic aromatic compounds formed by the fusion of a benzene ring with a chromene moiety [3]. The benzochromene structure is found in many natural products isolated from plants [4][5][6][7][8], lichens and fungi [9], and a wide range of biological activities such as antibacterial [5,10], antioxidant and anticancer activities have been reported for natural benzochromenes [9,11]. They have been reported to be able to intercalate with DNA [11,12], and to bind selectively to the estrogen receptor ERβ [13]. ...
    ... Benzochromenes are polycyclic aromatic compounds formed by the fusion of a benzene ring with a chromene moiety [3]. The benzochromene structure is found in many natural products isolated from plants [4][5][6][7][8], lichens and fungi [9], and a wide range of biological activities such as antibacterial [5,10], antioxidant and anticancer activities have been reported for natural benzochromenes [9,11]. They have been reported to be able to intercalate with DNA [11,12], and to bind selectively to the estrogen receptor ERβ [13]. ...
    ... They have been reported to be able to intercalate with DNA [11,12], and to bind selectively to the estrogen receptor ERβ [13]. Several cannabinoids are benzochromenes and bind to the cannabinoid receptors CB1 and CB2 [5,14]. This work focuses on the natural benzo[c]chromene pulchrol (1), isolated from the heptane fraction of the roots of Bourreria pulchra together with the corresponding aldehyde pulchral (5a) [4]. ...
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    Pulchrol (1) is a natural benzochromene isolated from the roots of Bourreria pulchra, shown to possess potent antiparasitic activity towards both Leishmania and Trypanozoma species. As it is not understood which molecular features of 1 are important for the antiparasitic activity, several analogues were synthesized and assayed. The ultimate goal is to understand the structure–activity relationships (SAR:s) and create a QSAR model that can be used for the development of clinically useful antiparasitic agents. In this study, we have synthesized 25 2-methoxy-6,6-dimethyl-6H-benzo[c]chromen analogues of 1 and its co-metabolite pulchral (5a), by semi-synthetic procedures starting from the natural product pulchrol (1) itself. All 27 compounds, including the two natural products 1 and 5a, were subsequently assayed in vitro for antiparasitic activity against Trypanozoma cruzi, Leishmania brasiliensis and Leishmania amazoniensis. In addition, the cytotoxicity in RAW cells was assayed, and a selectivity index (SI) for each compound and each parasite was calculated. Several compounds are more potent or equi-potent compared with the positive controls Benznidazole (Trypanozoma) and Miltefosine (Leishmania). The compounds with the highest potencies as well as SI-values are esters of 1 with various carboxylic acids.
  • ... Natural products have always been a rich source for the identification of antimicrobial drug candidates; thus, researchers have started to reinvestigate long known natural product-based drugs in order to provide solutions to the current antibiotic crisis [15][16][17][18][19][20][21][22]. Interestingly, different phytocannabinoids, natural product constituents of the extracts of the plant Cannabis sativa, which have so far mainly been associated with intoxication effects upon recreational usage and medical applications far beyond the treatment of infections, have been reported to show antibacterial activity against several Gram-positive bacterial pathogens, including MRSA [23][24][25][26][27][28][29]. ...
    ... In these studies, rather, single values of inconsistently screened different antimicrobial activities were reported, thus, clear structure-activity relationships are hard to conclude. In 2008, Appendino et al. [24] reported a more focused structure-activity relationship study on the anti-staphylococcal activity of different naturally occurring cannabinoids and synthetic derivatives against a broad range of various multi-drug resistant strains of S. aureus, including EMRSA-15, one of the main epidemic methicillin-resistant strains [141], SA-1199B, a multidrugresistant strain that possesses a gyrase mutation, and in addition overexpresses the NorA efflux mechanism [142], RN-4220, a macrolide-resistant strain [143], XU212, and a tetracycline-resistant strain overexpressing the TetK efflux pump [144], as summarized in Table 4. ...
    ... Interestingly, the synthetic isomers of CBD (Compound 64, Table 4, Entry 13) and CBG (Compound 65, Table 4, Entry 14), bearing the lipophilic side chain and one hydroxyl group in exchanged positions displayed potent activity comparable to their corresponding natural counterparts indicating that both moieties, although crucial for activity, can vary in their position at the phenolic core. A trend that has been observed for CBG-C1-type and CBC-type cannabinoid derivatives earlier [29], suggesting that they may rather serve as lipid affinity modulators influencing water solubility and cellular bioavailability [24]. ...
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    Novel antimicrobial drugs are urgently needed to counteract the increasing occurrence of bacterial resistance. Extracts of Cannabis sativa have been used for the treatment of several diseases since ancient times. However, its phytocannabinoid constituents are predominantly associated with psychotropic effects and medical applications far beyond the treatment of infections. It has been demonstrated that several cannabinoids show potent antimicrobial activity against primarily Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). As first in vivo efficacy has been demonstrated recently, it is time to discuss whether cannabinoids are promising antimicrobial drug candidates or overhyped intoxicants with benefits.
  • ... The combination of CBD and BAC is effective against Gram-positive bacteria. Initially, we validated the antimicrobial effect of cannabidiol (CBD) against the Gram-positive bacterium Methicillin-Resistant Staphylococcus aureus (MRSA) as previously published by Appendino and colleagues 14 but also for Enterococcus faecalis (E. faecalis), Listeria monocytogenes (L. ...
    ... The use of CBD and other cannabinoids as antibacterial agents was first described in 1976 by Van Klingeren and Ten Ham 13 and again in 2008 by Appendino and colleagues 14 , however, since then very little has been published on this topic. CBD is a quite effective antimicrobial compound with a MIC value of 4 µg/mL against S. aureus USA300 and other Gram-positive bacteria. ...
    ... CBD is a quite effective antimicrobial compound with a MIC value of 4 µg/mL against S. aureus USA300 and other Gram-positive bacteria. Appendino and colleagues 14 found MIC values of CBD extracted from powdered plant material in the 0.5-1 µg/mL range towards various drug-resistant strains of S. aureus. However, the mechanism or how CBD and other cannabinoids affects the bacteria has not been studied so far. ...
    Article
    Full-text available
    The cannabinoid cannabidiol (CBD) is characterised in this study as a helper compound against resistant bacteria. CBD potentiates the effect of bacitracin (BAC) against Gram-positive bacteria (Staphylococcus species, Listeria monocytogenes, and Enterococcus faecalis) but appears ineffective against Gram-negative bacteria. CBD reduced the MIC value of BAC by at least 64-fold and the combination yielded an FIC index of 0.5 or below in most Gram-positive bacteria tested. Morphological changes in S. aureus as a result of the combination of CBD and BAC included several septa formations during cell division along with membrane irregularities. Analysis of the muropeptide composition of treated S. aureus indicated no changes in the cell wall composition. However, CBD and BAC treated bacteria did show a decreased rate of autolysis. The bacteria further showed a decreased membrane potential upon treatment with CBD; yet, they did not show any further decrease upon combination treatment. Noticeably, expression of a major cell division regulator gene, ezrA, was reduced two-fold upon combination treatment emphasising the impact of the combination on cell division. Based on these observations, the combination of CBD and BAC is suggested to be a putative novel treatment in clinical settings for treatment of infections with antibiotic resistant Gram-positive bacteria.
  • ... Cannabidiol (CBD) is a phytocannabinoid from Cannabis sativa with anti-inflammatory (Martin-Moreno et al., 2011), anticancerous (Pisanti et al., 2017;Kosgodage et al., 2018) and anti-bacterial activity (Hernández-Cervantes et al., 2017). While immunoregulatory roles for cannabinoids have been reported in infectious disease (reviewed in Hernández-Cervantes et al., 2017), and C. sativa has been identified as a natural product with a capability of controlling bacterial infections, including a strong anti-bacterial activity against antibiotic resistant strains (Appendino et al., 2008), a link between CBD and bacterial MV release has hitherto not been investigated. ...
    ... Whether CBD may be utilized for combinatory application with such approaches may also be of putative interest, in addition to its observed effects in this study, in effectively reducing MV release. In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity (Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria (Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). ...
    ... In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity (Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria (Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). How precisely CBD may be working as an anti-bacterial agent is still not entirely clear (Appendino et al., 2008), particularly in the light of a plethora of targets for CBD (Ibeas Bih et al., 2015;Hernández-Cervantes et al., 2017), while structure-activity studies indicate that the ability of plant-derived phenolic compounds to interact with membranes and the existence of electrophilic functional groups are important (Miklasinska-Majdanik et al., 2018). ...
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    Membrane vesicles (MVs) released from bacteria participate in cell communication and host-pathogen interactions. Roles for MVs in antibiotic resistance are gaining increased attention and in this study we investigated if known anti-bacterial effects of cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, could be in part attributed to effects on bacterial MV release. We found that CBD is a strong inhibitor of MV release from Gram-negative bacteria (E. coli VCS257), while inhibitory effect on MV release from Gram-positive bacteria (S. aureus subsp. aureus Rosenbach) was negligible. When used in combination with selected antibiotics, CBD significantly increased the bactericidal action of several antibiotics in the Gram-negative bacteria. In addition, CBD increased antibiotic effects of kanamycin in the Gram-positive bacteria, without affecting MV release. CBD furthermore changed protein profiles of E. coli MVs after 1 h treatment. Our findings indicate that CBD may pose as a putative adjuvant agent for tailored co-application with selected antibiotics, depending on bacterial species, to increase antibiotic activity, including via MV inhibition, and help reduce antibiotic resistance. https://www.frontiersin.org/articles/10.3389/fcimb.2019.00324/abstract
  • ... Cannabidiol (CBD) is a phytocannabinoid from Cannabis sativa with anti-inflammatory (Martin-Moreno et al., 2011), anticancerous (Pisanti et al., 2017;Kosgodage et al., 2018) and anti-bacterial activity (Hernández-Cervantes et al., 2017). While immunoregulatory roles for cannabinoids have been reported in infectious disease (reviewed in Hernández-Cervantes et al., 2017), and C. sativa has been identified as a natural product with a capability of controlling bacterial infections, including a strong anti-bacterial activity against antibiotic resistant strains (Appendino et al., 2008), a link between CBD and bacterial MV release has hitherto not been investigated. ...
    ... Whether CBD may be utilized for combinatory application with such approaches may also be of putative interest, in addition to its observed effects in this study, in effectively reducing MV release. In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity (Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria (Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). ...
    ... In relation to antibiotic activity, cannabinoids including CBD, have been widely studied for their anti-bacterial activity (Wasim et al., 1995;Bass et al., 1996;Appendino et al., 2008;Hernández-Cervantes et al., 2017). For example, C. sativa extracts have previously been shown to have microbicidal activity on various Gram-positive bacteria, including several strains of S. aureus, as well as some Gram-negative bacteria (Wasim et al., 1995;Elphick, 2007;Nissen et al., 2010), with the minimum inhibitory concentrations (MIC) for the main phytocannabinoids, such as CBD, being in the 0.5-5 µM range, which is similar to many modern antibiotics (Van Klingeren and Ten Ham, 1976;Appendino et al., 2008). How precisely CBD may be working as an anti-bacterial agent is still not entirely clear (Appendino et al., 2008), particularly in the light of a plethora of targets for CBD (Ibeas Bih et al., 2015;Hernández-Cervantes et al., 2017), while structure-activity studies indicate that the ability of plant-derived phenolic compounds to interact with membranes and the existence of electrophilic functional groups are important (Miklasinska-Majdanik et al., 2018). ...
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    Membrane vesicles (MVs) released from bacteria participate in cell communication and host-pathogen interactions. Roles for MVs in antibiotic resistance are gaining increased attention and in this study we investigated if known anti-bacterial effects of cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, could be in part attributed to effects on bacterial MV release. We found that CBD is a strong inhibitor of MV release from Gram-negative bacteria (E. coli VCS257), while inhibitory effect on MV release from Gram-positive bacteria (S. aureus subsp. aureus Rosenbach) was negligible. When used in combination with selected antibiotics, CBD significantly increased the bactericidal action of several antibiotics in the Gram-negative bacteria. In addition, CBD increased antibiotic effects of kanamycin in the Gram-positive bacteria, without affecting MV release. CBD furthermore changed protein profiles of E. coli MVs after 1 h treatment. Our findings indicate that CBD may pose as a putative adjuvant agent for tailored co-application with selected antibiotics, depending on bacterial species, to increase antibiotic activity, including via MV inhibition, and help reduce antibiotic resistance.
  • ... Cross-resistance to microbial and plant antibacterial agents are rare, which is why plants are still an important source of antimicrobial agents [89]. Cannabis sativa is an herbaceous species that have been used in folk medicine. ...
    ... Appendino et al. investigated the antibacterial profile of these five alkylated and acylated cannabinoids and their carboxylic precursors "pre-cannabinoids" to obtain structure-activity data and to define the microbiocidal cannabinoid pharmacophore. The result showed that cannabinoids' antimicrobial activity depends on the modifications of the terpenoid moiety and their relation with the n-pentyl chain which affects lipid affinity and cellular bioavailability antimicrobial agents [89]. Chakraborty et al. also examined the antimicrobial activity of Cannabis sativa, Thuja orientalis, and Psidium guajava present in the leaf extracts were found to inhibit MRSA growth. ...
    ... C. Sativa plant is an important source that contains high concentrations of non-psychotropic cannabinoids, and therefore they can be used against MDR in MRSA strains and other pathogenic bacteria which make them attractive antibacterial leads. More studies are needed to establish safety and environmental profile of cannabinoids and the ability to use them systemically [89]. ...
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    The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.
  • ... Cannabinoids are divided into three groups on the basis of their source: endogenous or endocannabinoids (produced in humans and animals), synthetic (produced in the laboratory), and phytocannabinoids (uniquely from the cannabis plant) [16]. A few examples of cannabinoids are Δ-8-THC, cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC) [17]. These cannabinoids present in Cannabis are known for their antibacterial properties. ...
    ... These cannabinoids present in Cannabis are known for their antibacterial properties. It has been found that some cannabinoids, such as CBD, CBC, CBG, CBN, and Δ9-tetrahydrocannabinol (THC), exert antibacterial activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains [17]. Cannabidiol has been identified as a component of hemp oil that is effective against gram-positive bacteria and yeast [18]. ...
    Article
    Full-text available
    Background Dental plaque is a complex biofilm that gets formed on the teeth and acts as a reservoir of different microbes. It is the root cause for the occurrence of several dental problems and diseases, including cavities, bad breath, bleeding gums, tooth decay, and tooth loss. Therefore, it should be regularly removed using suitable oral care aids. Objectives The present study compared the efficacy of oral care products and cannabinoids in reducing the bacterial content of dental plaques. Methods Sixty adults aged 18 to 45 years were categorized into six groups based on the Dutch periodontal screening index. Dental plaques of the adults were collected using paro-toothpick sticks and spread on two Petri dishes, each with four divisions. On Petri dish-A, cannabidiol (CBD), cannabichromene (CBC), cannabinol (CBN), and cannabigerol (CBG) were used, and on Petri dish-B, cannabigerolic acid (CBGA), Oral B, Colgate, and Cannabite F (a toothpaste formulation of pomegranate and algae) were used. The Petri dishes were sealed and incubated, followed by counting the number of colonies. Results By evaluating the colony count of the dental bacteria isolated from six groups, it was found that cannabinoids were more effective in reducing the bacterial colony count in dental plaques as compared to the well-established synthetic oral care products such as Oral B and Colgate. Conclusion Cannabinoids have the potential to be used as an effective antibacterial agent against dental plaque-associated bacteria. Moreover, it provides a safer alternative for synthetic antibiotics to reduce the development of drug resistance.
  • ... To what extent this mixture of phytoconstituents plays in the safety and efficacy of CBD-rich FSHEs, particularly with regard to effects on the gut microbiome remains to be determined. This is important because multiple phytocannabinoids, including CBD, exhibit potent antibacterial activity in several models (Appendino et al. 2008;Hern andez-Cervantes et al. 2017), and their impact on the gut microbiome, whether positive or negative, could have significant health consequences. ...
    ... Recent product quality surveys imply that CBD exposure from commercially available dosage forms may either be enhanced or lessened due to discrepancies between product label claims and actual CBD content. In addition, several phytocannabinoids have been shown to possess potent antibacterial properties (Appendino et al. 2008;Hern andez-Cervantes et al. 2017). Taken together, these elements prompted us to investigate the effects of prolonged CRCE administration on gut toxicology and ecology. ...
    Article
    Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated certain C. sativa plant material as “hemp,” thus removing it from the DEA’s list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. The goal of this study was to investigate the effects of a cannabidiol-rich cannabis extract (CRCE) on the gut microbiome and associated histomorphological and molecular changes in the mouse gut mucosa. Male C57BL6/J mice were gavaged with either 0, 61.5, 184.5, or 615 mg/kg/bw of CRCE in sesame oil for 2 weeks (Mon–Fri). Substantial CRCE-induced increases in the relative abundance of A. muciniphila, a bacterial species currently accepted as probiotic, was observed in fecal samples at all doses. This was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines—Il1ß, Cxcl1, and Cxcl2 in the colon tissue. Furthermore, dramatic increases in the relative abundance of A. muciniphila significantly decreased expression of Muc2—a gene intimately associated with gut integrity. Taken together, these findings raise concerns about the safety of long-term CBD usage and underline the need for additional well-designed studies into its tolerability and efficacy.
  • ... On the contrary, much less is known about its effects on prokaryotes. A previous study showed that CBG displays antibacterial properties against methicillin-resistant Staphylococcus aureus strains (Appendino et al., 2008). Here we tested the anti-quorum sensing and antibiofilm formation potential of CBG on V. harveyi. ...
    ... So far, the activities of CBG have mainly been studied in eukaryotes where it has been found to be neuroprotective, acting as an anti-oxidant (Giacoppo et al., 2017) and exert anti-inflammatory activities (Eisohly et al., 1982). CBG has previously been found to display anti-bacterial properties toward clinical isolates of methicillin-resistant Staphylococcus aureus (Appendino et al., 2008). However, its effect on the bacterial QS pathway has remained unknown. ...
    Article
    Full-text available
    Cannabigerol (CBG) is a non-psychoactive cannabinoid naturally present in trace amounts in the Cannabis plant. So far, CBG has been shown to exert diverse activities in eukaryotes. However, much less is known about its effects on prokaryotes. In this study, we investigated the potential role of CBG as an anti-biofilm and anti-quorum sensing agent against Vibrio harveyi. Quorum sensing (QS) is a cell-to-cell communication system among bacteria that involves small signaling molecules called autoinducers, enabling bacteria to sense the surrounding environment. The autoinducers cause alterations in gene expression and induce bioluminescence, pigment production, motility and biofilm formation. The effect of CBG was tested on V. harveyi grown under planktonic and biofilm conditions. CBG reduced the QS-regulated bioluminescence and biofilm formation of V. harveyi at concentrations not affecting the planktonic bacterial growth. CBG also reduced the motility of V. harveyi in a dose-dependent manner. We further observed that CBG increased LuxO expression and activity, with a concomitant 80% downregulation of the LuxR gene. Exogenous addition of autoinducers could not overcome the QS-inhibitory effect of CBG, suggesting that CBG interferes with the transmission of the autoinducer signals. In conclusion, our study shows that CBG is a potential anti-biofilm agent via inhibition of the QS cascade.
  • ... Cannabinoids are phytochemicals / secondary metabolites naturally produced by cannabis plant (Cannabis sativa L.) which include some psychoactive compounds such as Δ9-tetrahydrocannabinol (Δ9-THC) and various non-psychoactive compounds such as cannabichromene (CBC), cannabidiol (CBD), cannabigerol (CBG) and cannabinol (CBN) (Andre et al. 2016;Pellati et al. 2018). Cannabinoids are reported to have antibacterial activity against several gram-positive as well as gram-negative bacterial species (Wasim et al. 1995;Appendino et al. 2008;Sarmadyan et al. 2014;Kosgodage et al. 2019). An interesting detailed molecular study reported that synthetic cannabinoid interferes in AI-2 quorum sensing signal cascade in Vibrio harveyi (Soni et al. 2015). ...
    ... Cannabinoids, the secondary metabolites produced by Cannabis sativa L. plant are gaining enormous research interest in the recent past due to its various beneficial properties in the field of pharmaceutical and cosmetic industry. In addition, the antibacterial properties of cannabis essential oils and cannabinoids are also being reported (Appendino et al. 2008;Iseppi et al. 2019) including antibacterial activity against methicillinresistant Staphylococcus aureus (MRSA) (Farha et al. 2020). A synthetic cannabinoid HU-210 has been demonstrated to have inhibitory effect on quorum sensing (QS) and QS-dependent virulence properties in Vibrio harveyi (Soni et al. 2015). ...
    Article
    Full-text available
    Abstract Background: Dental plaque is a global health problem affecting people of various age groups. Cannabinoids aregaining enormous research attention due to its beneficial properties for various applications. A preliminaryobservation on antimicrobial property of cannabinoids against dental plaque bacteria has been reported recently.As a follow-up research, here we report the in vitro evaluation of cannabinoids infused mouthwash productsagainst total culturable (aerobic) bacterial content from dental plaque samples. Methods: We tested two cannabinoid-infused mouthwash products containing cannabidiol (CBD) andcannabigerol (CBG) respectively (each mouthwash containing < 1% cannabinoid by weight) in vitro against total-culturable bacteria from dental plaque samples collected from 72 adults aged between 18 and 83 years. Theparticipants were grouped on the basis of Dutch periodontal screening index (DPSI) score. To compare the efficacyof our products, we included two most commonly available products over the counter (Product A and Product B) to represent commercially available mouthwash products and the gold standard chlorhexidine digluconate 0.2% asa positive control. The product A represents mouthwash containing essential oils and alcohol, and Product Brepresents alcohol-free mouthwash that contains fluoride. All the mouthwash products were evaluated directly assuch without any dilution through disc diffusion and agar well diffusion approaches and the diameter of zone ofinhibition was measured. The limitation in methodology was that, the samples were open-label and the personwho performed the manual measurements was unblind to test and control products used. Results: On average, the cannabinoids infused mouthwash products showed the similar bactericidal efficacy as thatof chlorhexidine 0.2%. Both chlorhexidine 0.2% and cannabinoids infused mouthwash products were effectiveagainst all the samples tested. Product A did not show any significant antimicrobial activity in any of the samplestested, except that a very marginal inhibition with a zone of 7-8 mm was observed only in 9 samples. Product B didnot show any detectable inhibition zone at all in any of the samples tested. The ranges of zones of inhibition (andtheir average) were 8–25 mm (18.1 mm) for CBD-mouthwash, 8–25 mm (17.7 mm) for CBG-mouthwash; 12–25 mm(16.8 mm) for chlorhexidine 0.2%; 0–8 mm (0.1 mm) for Product A; and 0 mm for Product B. Although the differencein performance was slightly higher than chlorhexidine in both the cases, the difference was statistically significantfor CBD-mouthwash and near significant for CBG-mouthwash. No significant difference was observed between CBD- and CBG-mouthwash. No significant difference in performance was found between DPSI score groups for anyof the product tested. To our knowledge this is the first report on such efficient mouthwash product with naturalkey ingredients including cannabinoids and without any kind of fluoride or alcohol. Conclusions: Our in vitro results demonstrate the potential of cannabinoids in developing efficient and safermouthwash products and next generation oral care products without fluoride and alcohol. Keywords: Cannabinoids, CBD, CBG, Oral care, Dental plaque, Oral health, Mouthwash
  • ... However, research supporting such "protective effects" of CBD is extremely limited. In fact, the authors identified only two (in vitro) studies reporting antimicrobial effects [5,179] and two (in vitro) studies reporting anti-viral effects [119,122] (see Tagne et al. [167] and Nichols et al. [136] for reviews). In the former, CBD demonstrated anti-microbial activity against various strains of Staphylococcus aureus [5,179], as well as Staphylococcus pyogenes, Staphylococcus milleri, and Staphylococcus faecalis [179] at minimum concentrations of~3.2-15.9 ...
    ... In fact, the authors identified only two (in vitro) studies reporting antimicrobial effects [5,179] and two (in vitro) studies reporting anti-viral effects [119,122] (see Tagne et al. [167] and Nichols et al. [136] for reviews). In the former, CBD demonstrated anti-microbial activity against various strains of Staphylococcus aureus [5,179], as well as Staphylococcus pyogenes, Staphylococcus milleri, and Staphylococcus faecalis [179] at minimum concentrations of~3.2-15.9 μM; however, one study also found that these effects were virtually abolished when the original media (a nutrient broth agar) was replaced with one containing 5% blood (increasing the minimum concentration to~160 μM CBD) [179]. ...
    Article
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    Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
  • ... Cannabis, also known as marijuana, hemp, or hashish, is derived from the plant Cannabis sativa, Cannabis indica and Cannabis ruderalis, and is one of the most widely used recreational substance [18,19]. Cannabis extracts, especially its cannabidiol content has anti-bacterial properties [20], including toxicity against Staphylococcus aureus [21], protection from endotoxin induced septic shock [22], reduction of neurological damage from Streptococcal pneumonia meningitis [23], and inhibition of Clostridioides difficile in invitro model studies [24]. Cannabidiol attenuates Clostridioides difficile toxin induced enterocyte apoptosis, and enhances the maintenance of gut integrity [25]. ...
    Article
    Background: The prevalence of Clostridioides difficile Infection (CDI), the most notorious hospital acquired disease, and of excessive cannabis use (cannabis use disorder (CUD)) have both been steadily rising. Although cannabidiol, an active ingredient of cannabis, maintains gut integrity and suppresses entero-toxins from Clostridioides difficile, the relationship between CUD and CDI has not been studied. Methods: We selected adult records (age ≥ 18 years) from the Nationwide Inpatient Sample 2014, and identified CUD and other clinical conditions using ICD-9-CM codes. We used propensity scores derived from a multivariate logistic model to match CUD to non-CUD in a 1:1 ratio (29,912:29,912). We estimated the relative risk for CDI using log-binomial regression models with generalized estimating equations [SAS 9.4]. Results: Among the matched hospitalizations (n = 59,824), cannabis usage was associated with a reduced prevalence of CDI (prevalence: 455.5 [95% CI: 385.1-538.8] vs. 636.4 [95% CI: 549.9-736.5] per 100,000 hospitalizations), resulting in a 28% reduced risk of CDI (relative risk: 0.72 [95% CI: 0.58-0.88]; p = 0002). Non-dependent and dependent CUD respectively had 23% and 80% reduced likelihood of CDI when compared to non-cannabis users (0.77 [95% CI: 0.60-0.95] and 0.20 [95% CI: 0.06-0.54]; p < 0.05). Furthermore, dependent users had less risk of CDI compared to non-dependent users (0.26 [95% CI: 0.08-0.88]; p = 0.01). Conclusions: CUD was associated with a decreased risk of CDI amongst hospitalized patients. Prospective and molecular mechanistic studies are required to elucidate how cannabis and its contents impacts CDI.
  • ... Antibacterial Assay. The antibacterial activity of the isolated compounds was determined using the conventional broth dilution assay [31] with ciprofloxacin (CIP) as a positive control. Sixteen pathogenic bacterial strains were used, including Bacillus megaterium, Bacillus subtilis, Escherichia coli, Bacillus anthraci, Bacillus cereus, Bacterium paratyphosum B, Enterobacter aerogenes, Micrococcus lysodeikticus, Micrococcus luteus, Proteusbacillm vulgaris, Shigella dysenteriae, Psmdomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Vibrio anguillarum, and Vibrio parahemolyticus. ...
    Article
    Full-text available
    Identification and analysis of the whole genome of the marine-derived fungus Penicillium brasilianum HBU-136 revealed the presence of an interesting biosynthetic gene cluster (BGC) for non-ribosomal peptide synthetases (NRPS), highly homologous to the BGCs of indole-diketopiperazine derivatives. With the aid of genomic analysis, eight indole-diketopiperazines (1−8), including three new compounds, spirotryprostatin G (1), and cyclotryprostatins F and G (2 and 3), were obtained by large-scale cultivation of the fungal strain HBU-136 using rice medium with 1.0% MgCl2. The absolute configurations of 1−3 were determined by comparison of their experimental electronic circular dichroism (ECD) with calculated ECD spectra. Selective cytotoxicities were observed for compounds 1 and 4 against HL-60 cell line with the IC50 values of 6.0 and 7.9 μM, respectively, whereas 2, 3, and 5 against MCF-7 cell line with the IC50 values of 7.6, 10.8, and 5.1 μM, respectively.
  • ... Cannabidiol (CBD) is known to exert strong anti-inflammatory and anti-nociceptive properties [1]- [6], besides its well-known anti-microbial activities [7]. In addition, CBD has been shown to be neuroprotective and possess anti-oxidative activities [8]. ...
  • ... Suppress the Growth of P. gingivalis and F. alocis but Not T. denticola Cannabinoids have, historically, been ascribed antimicrobial properties (45)(46)(47). Therefore, we firstly examined the influence of marijuana-derived cannabinoid-subtypes on three important oral pathogens. ...
    Article
    Full-text available
    Cannabis use is an emergent risk factor for periodontitis, a chronic bacterial-induced disease of the supporting structures of the teeth. However, the mechanisms by which marijuana exposure predisposes to periodontal tissue destruction have yet to be elucidated. Therefore, we examined the influence of physiologically relevant doses of major marijuana-derived phytocannabinoid subtypes (cannabidiol [CBD]; cannabinol [CBN]; and tetrahydrocannabinol [THC], 1.0 μg/ml) on the interactions of three ultrastructurally variant oral pathogens, Porphyromonas gingivalis, Filifactor alocis, and Treponema denticola with the immune system. CBD, CBN, and THC each suppressed P. gingivalis-induced IL-12 p40, IL-6, IL-8, and TNF release while enhancing the anti-inflammatory cytokine, IL-10, from human innate cells. Similar phenomena were observed in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. Higher phytocannabinoid doses (≥5.0 μg/ml) compromised innate cell viability and inhibited the growth of P. gingivalis and F. alocis, relative to unexposed bacteria. T. denticola, however, was resistant to all cannabinoid doses tested (up to 10.0 μg/ml). Pharmaceutical inhibition and efficient gene silencing indicated that a common CB2/PI3K axis of immune suppression is triggered by phytocannabinoids in vitro. This pathway does not appear to perpetuate through the canonical GSK3β-dependent cholinergic anti-inflammatory pathway, the predominant endogenous inflammatory control system. In a repetitive, transient oral infection model, CBD also suppressed P. gingivalis-induced innate immune markers in wild-type mice, but not in CB2−/− mice. If such phenomena occur in humans in situ, environmental cannabinoids may enhance periodontitis via direct toxic effects on specific oral bacteria; by compromising innate cell vitality; and/or through a suppressed innate response to periodontal pathogens involving a CB2/PI3K signaling lineage.
  • ... Among these compounds, cannabidiol (CBD) represents the most promising substance from a pharmaceutical point of view. It shows antioxidant, anti-inflammatory, antibacterial, anti-proliferative and neuroprotective properties (Appendino et al., 2008). ...
    Conference Paper
    Full-text available
    The researches on Cannabis sativa L. (fiber-type industrial hemp) have been significantly increasing in recent years especially in the field of health, medicine, nutrition, agriculture, biomaterial as well as textile. Although fiber-type industrial hemp is using in textile industry, there hasn’t been found any literature about the usage possibilities of hemp in leather manufacturing. For this purpose, the present work was aimed to evaluate the potential applications of fiber-type industrial hemp for leather industry. First, root, stem and fiber parts of the plant were investigated in terms of tannin content as the residues of the hemp. The results showed that root and stem parts have low phenolic content, but fibers of the plant have a great potential in the use of leather production and can be evaluated in different processing steps such as tanning and retanning. Besides, the antimicrobial activity of the hemp fabrics was determined with five different microorganisms due to the demonstration of potential antimicrobial effect of the hemp extracts that will be used in the leather production. Additionally, fabrics of hemp can be also used in leather products as auxiliary material by means of the promising properties in literature and clothing hygiene and will be evaluated in the manufacturing of lining materials for footwear. Still our work is continuing to search the potential alternatives of this current strategic plant.
  • ... The bioactive components of C. sativa were found in greater concentrations in flowers, as compared to seeds (Latta and Eaton 1975). The antibacterial properties of C. sativa are attributed to cannabinoids such as CBD (Appendino et al. 2008), which is present in low quantities in seed oil as compared to the rest of the plant (Leizer et al. 2000). ...
    Article
    Full-text available
    Current methodologies for evaluation of antibacterial properties of traditional textiles are not applicable to foil-backed, poorly-absorbent electrospun nanofiber materials, since existing test methods require absorbent fabrics. Since electrospun nanofibers are adhered to the foil backing only by electrostatic interactions, methods used to evaluate antibacterial properties of surfaces cannot be used because these protocols cause the nanofibers to lift from the foil backing. Therefore, a novel method for measurement of the antibacterial properties of electrospun metallic foil-backed nanofiber materials was developed. This method indicated that acetate-based nanofibers manufactured to contain 5 to 30 weight percent of cold-pressed hemp seed oil or full-spectrum hemp extract inhibited the growth of Staphylococcus aureus in a dose-dependent manner, from 85.3% (SEM = 2.2) inhibition to 99.3% (SEM = 0.15) inhibition, respectively. This testing method represents an advanced manufacturing prototype procedure for assessment of antibacterial properties of novel electrospun, metallic foil-backed nanofiber materials.
  • ... Sphagnum and medicinal plants, all m/z values from Sphagnum fallax were cross-checked against a database of antimicrobial compounds confirmed in the FTICR-MS analysis of the tested medicinal plants. The m/z of 17 known antimicrobial chemical compounds(Abedini et al., 2013;Akroum, Bendjeddou, Satta, & Lalaoui, 2009;Appendino et al., 2008;Bai et al., 2018;Chiruvella, Mohammed, Dampuri, Ghanta, & Raghavan, 2007;del Valle et al., 2016;Fiamegos et al., 2011;Huang, George, & Ebersole, 2010;Kandakumar & Manju, 2017;Lou et al., 2012;Mazimba, 2017;Nakatsuji et al., 2009;Narasimhan, Ohlan, Ohlan, Judge, & Narang, 2009;Sati, Dhyani, Bhatt, & Pandey, 2019;Shi et al., 2016;Singh, Sharma, Rani, Mishra, & Sharma, 2011) were confirmed to be present within Sphagnum. ...
    Article
    Full-text available
    Sphagnum mosses dominate peatlands by employing harsh ecosystem tactics to prevent vascular plant growth and microbial degradation of these large carbon stores. Knowledge about Sphagnum‐produced metabolites, their structure and their function, is important to better understand the mechanisms, underlying this carbon sequestration phenomenon in the face of climate variability. It is currently unclear which compounds are responsible for inhibition of organic matter decomposition and the mechanisms by which this inhibition occurs. Metabolite profiling of Sphagnum fallax was performed using two types of mass spectrometry (MS) systems and 1H nuclear magnetic resonance spectroscopy (1H NMR). Lipidome profiling was performed using LC‐MS/MS. A total of 655 metabolites, including one hundred fifty‐two lipids, were detected by NMR and LC‐MS/MS—329 of which were novel metabolites (31 unknown lipids). Sphagum fallax metabolite profile was composed mainly of acid‐like and flavonoid glycoside compounds, that could be acting as potent antimicrobial compounds, allowing Sphagnum to control its environment. Sphagnum fallax metabolite composition comparison against previously known antimicrobial plant metabolites confirmed this trend, with seventeen antimicrobial compounds discovered to be present in Sphagnum fallax, the majority of which were acids and glycosides. Biological activity of these compounds needs to be further tested to confirm antimicrobial qualities. Three fungal metabolites were identified providing insights into fungal colonization that may benefit Sphagnum. Characterizing the metabolite profile of Sphagnum fallax provided a baseline to understand the mechanisms in which Sphagnum fallax acts on its environment, its relation to carbon sequestration in peatlands, and provide key biomarkers to predict peatland C store changes (sequestration, emissions) as climate shifts.
  • ... 26 Cannabis sativa L. Antidepressant [158], anti-nausea [159], antinociceptive [160], anti-inflammatory & anti-HIV-1 [161], immunomodulatory [162], anticancer [163], antibacterial [164]. Phytocannabinoids e.g. ...
    Article
    Introduction: People living with HIV/AIDS (PLHIV) widely use medicinal plants for boosting immunity and managing infections. The aim of this study was to document the medicinal plant species used by herbalists to boost the immune system of people living with HIV/AIDS in Uganda. Materials and methods: Semi-structured questionnaires were administered to 90 herbalists to obtain ethnobotanical information on medicinal plant species used in different parts of Uganda. A detailed literature review of the pharmacology, phytochemistry, toxicology and other traditional used of the documented medicinal plants was also conducted. Results: Seventy-one medicinal plant species from 37 families and 64 genera were identified. Trees contributed 38.0 % of the species used and herbs 35.2 %. The majority of the herbal medicines were made from leaves (35.6 %), bark (24.1 %) and roots (20.7 %). Zanthoxylum chalybeum Engl. and Psidium guajava L. were the most widely used species with citation frequencies (CF) of 11 each. These were followed by Warburgia ugandensis Sprague, Acacia hockii De Wild. and Bridelia micrantha (Hochst.) Baill (CF = 8 each), Mangifera indica L., Markhamia lutea (Benth.) K. Schum., Aloe vera (L.) Burm.f. and Erythrina abyssinica DC. (CF = 7 each). Most traditional medicine practitioners (TMP) (85.6%) used herbs for boosting immunity for PLHIV, whether or not the patients were on antiretroviral treatment. The patients often disclosed their sero-status to the TMP who considered all PLHIV to be immunocompromised. Conclusion: Herbalists widely prescribe medicinal plant species for boosting or restoring the immunity in PLHIV in Uganda. Keywords: Medicinal plantsEthnobotanical surveyImmunomodulationHerbalistsHIV/AIDSUganda
  • ... Chiurchiu et al., in a similar study, proved a decrease in the IL-6, IL-12, and IFN-α levels in dendritic cells [45]. In regard with the antimicrobial activity of Cannabis sativa extracts, studies have reported antimicrobial characteristics targeting gram-positive (Staphylococcus aureus, Micrococcus flavus, and Baccilus subtilus) and gramnegative bacteria (Proteus vulgaris and Pseudomonas savastanoe), as well as an antifungal activity (Aspergilus niger) [40,[78][79][80][81]. Appendino et al. also proved an increased antimicrobial activity for Δ9-THC and CBD on Staphylococcus aureus [82]. A similar study was carried out by Bass et al., who reported a significant decrease in neurological damage inflicted by infections with Streptococcus pneumoniae following long-term CBD administration [83]. ...
    Preprint
    Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahidrocannabinol and cannabinol have been noticed. The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.
  • ... However, this methodology overcomes the common problems in the trials of synthetic biology of natural products which may be harmful to host organisms 25 . Such problems are especially true for defence-related toxic compounds, including cannabinoids, which could be toxic both in prokaryotic and eukaryotic cell cultures 34,41 . Thus, the synthetic biochemistry approach might be superior to synthetic biology, especially in the case of producing toxic natural products. ...
  • ... Chiurchiu et al., in a similar study, proved a decrease in the IL-6, IL-12, and IFN-α levels in dendritic cells [45]. In regard with the antimicrobial activity of Cannabis sativa extracts, studies have reported antimicrobial characteristics targeting gram-positive (Staphylococcus aureus, Micrococcus flavus, and Baccilus subtilus) and Gram-negative bacteria (Proteus vulgaris and Pseudomonas savastanoe), as well as an antifungal activity (Aspergilus niger) [40,[78][79][80][81]. Appendino et al. also proved an increased antimicrobial activity for ∆9-THC and CBD on Staphylococcus aureus [82]. A similar study was carried out by Bass et al., who reported a significant decrease in neurological damage inflicted by infections with Streptococcus pneumoniae following long-term CBD administration [83]. ...
    Article
    Full-text available
    Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis. One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been noticed. One of the most important is their ability to reduce the biosynthesis of pro-inflammatory mediators and the modulation of immune mechanisms. Different studies have reported that cannabinoids can reduce oxidative stress at mitochondrial and cellular levels. The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.
  • ... This considerable bacterial decline in the CT-PES hybrid membranes when compared to the pure PES membranes was attributable to the synergistic antibacterial activity of cannabinoids and terpenes ( Figure 6), which has not only been reported in the present research, but also reported previously [39,40]. In addition to this, the antibacterial properties of the CT PES membranes could also be attributable to a rise in hydrophilicity, which may lead to lower the attachment of Gram-positive and Gram-negative bacteria on the membrane surface [41]. ...
    Article
    Full-text available
    Plant phytochemicals have potential decontaminating properties, however, their role in the amelioration of hydrophobic water filtration membranes have not been elucidated yet. In this work, phytochemicals (i.e., cannabinoids (C) and terpenes (T) from C. sativa) were revealed for their antibacterial activity against different Gram-positive and Gram-negative bacteria. As such, a synergistic relationship was observed between the two against all strains. These phytochemicals individually and in combination were used to prepare polyethersulfone (PES) hybrid membranes. Membrane characterizations were carried out using scanning electron microscopy, Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy. Moreover, contact angle, water retention, surface roughness, mechanical testing, and X-ray florescence analysis were also carried out. According to results, the CT-PES hybrid membrane exhibited the lowest contact angle (40°), the highest water retention (70%), and smallest average pore size (0.04 µm). The hybrid membrane also exhibited improved water flux with no surface leaching. Quantitative bacterial decline analysis of the CT-PES hybrid membranes confirmed an effective antibacterial performance against Gram-positive and Gram-negative bacteria. The results of this study established cannabinoids and terpenes as an inexpensive solution for PES membrane surface modification. These hybrid membranes can be easily deployed at an industrial scale for water filtration purposes.
  • ... Appendino et al. investigated the antibacterial activity of five major cannabinoids and their analogs against a range of MDR S. aureus isolates [60]. It was found that cannabidiolic acid (CBDA) possesses good antimicrobial activity (MIC = 2 μg/mL, 8), which was further improved with omission of the carboxylate moiety (9). ...
    Article
    A post-antibiotic world is fast becoming a reality, given the rapid emergence of pathogens that are resistant to current drugs. Therefore, there is an urgent need to discover new classes of potent antimicrobial agents with novel modes of action. Cannabis sativa is an herbaceous plant that has been used for millennia for medicinal and recreational purposes. Its bioactivity is largely due to a class of compounds known as cannabinoids. Recently, these natural products and their analogs have been screened for their antimicrobial properties, in the quest to discover new anti-infective agents. This paper seeks to review the research to date on cannabinoids in this context, including an analysis of structure–activity relationships. It is hoped that it will stimulate further interest in this important issue.
  • ... This considerable bacterial decline in the CT-PES hybrid membranes when compared to the pure PES membranes was attributable to the synergistic antibacterial activity of cannabinoids and terpenes ( Figure 6), which has not only been reported in the present research, but also reported previously [39,40]. In addition to this, the antibacterial properties of the CT PES membranes could also be attributable to a rise in hydrophilicity, which may lead to lower the attachment of Gram-positive and Gram-negative bacteria on the membrane surface [41]. ...
  • ... Cannabis sativa is a tall, thin-leafed plant that can grow 5e18 feet tall and is often branchless [5]. Recent pharmacological studies have indicated that Cannabis has a variety of properties, such as analgesic [6], antibacterial [7], anti-inflammatory [8], anti-allergic [9], anti-hypertensive and anti-thrombotic effects [10]. Clinically, unofficially approved cannabis has been widely used for neurological diseases and antitumour applications [11,12]. ...
  • ... Contrary to some earlier findings, accumulating experimental evidence now strongly suggests that cannabidiolic acid (CBDA) (Fig. 1A), a constituent of the fiber-type cannabis plant, is a biologically active component. For example, CBDA is reported to exert anti-bacterial effects (Appendino et al., 2008), cyclooxygenase-2 (COX-2) enzyme inhibition (Takeda et al., 2008;Takeda, 2013), down-regulation of COX-2 expression (Takeda et al., 2014aSuzuki et al., 2017), and anti-nausea/emetic effects (Bolognini et al., 2013;Rock and Parker, 2013). ...
    Article
    A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities. We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer. Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established. It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is “no” modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells. We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2. These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.
  • ... Compound 21 showed a good activity against Leishmania mexicana (IC 50 = 4.6 μg/ml) and Trypanosoma cruzi (IC 50 = 7.5 μg/ml) (Erosa-Rjon et al. 2010), while compound 22 was found to be inactive. ∆ 9 -Tetrahydrocannabinols (23) and cannabinol (24) were isolated from Cannabis sativa (Marijuana plant) and were observed to display very good anti-microbial effect against different drug-resistant strains of S. aureus (XU212, ATCC25923, RN-4220, EMRSA-15, EMRSA-16 and SA-1199B) in a MIC range of 2-0.5 μg/ ml (Appendino et al. 2008). Methyl-5,10-dihydroxy-7-methoxy-3-methyl-3-[4methyl-3-pentenyl]-3H-benzo[f]chromene-9-carboxylate (25), a homoprenylated benzochromene, was isolated for the first time from the solvent (hexane) extract of Pentas bussei plant roots. ...
    Chapter
    Chromenes (benzopyrans) are privileged scaffolds that are widely distributed in a plethora of biologically active natural products, drugs and therapeutic leads. 2H-Chromenes and their benzofused derivatives are extensively distributed in nature and are considered essential for the development of new therapeutic agents for a variety of diseases. The chromene nucleus is a vital constituent of various naturally occurring and synthetic molecules with a broad range of bioactivities, such as anti-vascular, anti-microbial, antioxidant, anti-tumour, antifungal, antiviral, anti-cancer, anti-HIV, anti-tubercular, anti-coagulant, anti-inflammatory, oestrogenic, analgesic, anti-helminthic, herbicidal, anti-convulsant and anti-spasmolytic activity. Chromene constitutes the fundamental skeleton of different types of natural alkaloids, coumarins, flavonoids, polyphenols, anthocyanins and tocopherols. Recently, naturally occurring chromenes, such as wittifurans A, D, E and F, gramniphenol C, F and G, (+)-psiguadial B, parvinaphthol C, busseihydroquinone E, anthopogochromane A–C, tuberatolide B, (R)-sargachromenol, (S)-sargachromenol, obovatin, chalcones, flemingins A–C, G and H, soulamarin, lindbergin E–F and flemiphilippinones C have been isolated from various plants. This chapter not only critically reviews the recent literature reports on chromene as a privileged scaffold in medicinal chemistry, particularly, 2,2-dimethyl-2H-chromenes, natural benzochromenes and fused chromenes, but also highlights the need for further research on reported and new chromene-based phytomolecules to evaluate their possible therapeutic applications, and toxicological and particular genotoxic profiles against a wide range of diseases, especially cancer, drug-resistant microbial infections and lethal viral diseases.
  • ... Antifungal activities were evaluated using the conventional broth dilution assay (Appendino et al., 2008). Five phytopathogenic fungal strains, including Botrytis cinerea, Magnaporthe grisea, Phytophthora parasitica, Pestallozzia theae, and Valsa mali were used. ...
    Article
    Full-text available
    A new polyketide derivative, nafuredin C (1), a novel heterocyclic dipeptide, trichodermamide G (3), together with four known biogenetically related compounds nafuredin A (2), trichodermamide A (4), aspergillazin A (5), and peniisocoumarin H (6), were isolated from the mangrove-derived fungus Trichoderma harzianum D13. Their structures, including their absolute configurations, were determined by spectroscopic analysis and time-dependent density functional theory-electronic circular dichroism (ECD) calculations. Trichodermamide G was found to be a novel epithiodiketopiperazine derivative with an unprecedented cyclic system containing a sulfur bridge, and nafuredin C represented the third nafuredin derivative of these homologous compounds. The new compound nafuredin C exhibited obvious antifungal activity against Magnaporthe oryzae with a minimum inhibitory concentration (MIC) of 8.63 μM, which is on the same order of magnitude as the positive control carbendazim (MIC = 3.27 μM).
  • ... Later on, the roles of the endocannabinoid system in the induction of immunity by bacterial pathogens were established [65] and specific CB2 genotypes were found to correlate with susceptibility to some viral diseases [36, 66,67]. On the other hand, in vitro studies demonstrated that cannabinoids exert microbicidal activity on different bacteria and fungi [65,68] and could also control viral pathogenesis in some cases [69][70][71]. In a murine model for Malaria, oral administration of Cannabis increased the survival of infected mice [72]. ...
    Article
    Full-text available
    The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions.
  • ... Among those are cannabidiol and cannabinoic acids, whose MoA are yet unknown (Di Marzo et al., 2004). Several cannabinoids (e.g., 9 -THC, CBD, CBC, CBG, CBN), exhibit antibiotic activity to Staphylococcus aureus, highly correlated to the stereochemistry of the molecules and the groups of substitution (Appendino et al., 2008). ...
    Article
    Full-text available
    Cannabis (Cannabis sativa L.) is a complex, polymorphic plant species, which produces a vast array of bioactive metabolites, the two major chemical groups being cannabinoids and terpenoids. Nonetheless, the psychoactive cannabinoid tetrahydrocannabinol (Δ 9 -THC) and the non-psychoactive cannabidiol (CBD), are the two major cannabinoids that have monopolized the research interest. Currently, more than 600 Cannabis varieties are commercially available, providing access to a multitude of potent extracts with complex compositions, whose genetics are largely inconclusive. Recently introduced legislation on Cannabis cultivation in many countries represents a great opportunity, but at the same time, a great challenge for Cannabis research and development (R&D) toward applications in the pharmaceutical, food, cosmetics, and agrochemical industries. Based on its versatility and unique capabilities in the deconvolution of the metabolite composition of complex matrices, metabolomics represents an ideal bioanalytical tool that could greatly assist and accelerate Cannabis R&D. Among others, Cannabis metabolomics or cannabinomics can be applied in the taxonomy of Cannabis varieties in chemovars, the research on the discovery and assessment of new Cannabis-based sources of bioactivity in medicine, the development of new food products, and the optimization of its cultivation, aiming for improvements in yield and potency. Although Cannabis research is still in its infancy, it is highly foreseen that the employment of advanced metabolomics will provide insights that could assist the sector to face the aforementioned challenges. Within this context, here, the current state-of-the-art and conceptual aspects of cannabinomics are presented.
  • ... Moreover, AEA has been shown to diminish the inflammatory response in periodontitis [19]. A few studies have reported the antimicrobial effects of cannabis extracts against different pathogens [20], and anti-MRSA activity of exogenous cannabinoids [21]. In addition, we have shown that single AEA and AraS effectively alter the pathogenicity of different MRSA strains [22]. ...
    Article
    Full-text available
    Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Our previous study showed antimicrobial effects of anandamide (AEA) and arachidonoyl serine (AraS) against methicillin (MET)-resistant S. aureus (MRSA) strains, proposing the therapeutic potential of these endocannabinoid/endocannabinoid-like (EC/EC-like) agents for the treatment of MRSA. Here, we investigated the potential synergism of combinations of AEA and AraS with different types of antibiotics against MRSA grown under planktonic growth or biofilm formation. The most effective combinations under planktonic conditions were mixtures of AEA and ampicillin (AMP), and of AraS and gentamicin (GEN). The combination with the highest synergy in the biofilm formation against all tested bacterial strains was AEA and MET. Moreover, the combination of AraS and MET synergistically caused default of biofilm formation. Slime production of MRSA was also dramatically impaired by AEA or AraS combined with MET. Our data suggest the novel potential activity of combinations of EC/EC-like agents and antibiotics in the prevention of MRSA biofilm formation.
  • ... The antibacterial and antifungal activity was evaluated by the conventional broth dilution assay (Appendino et al., 2008). ...
    Article
    Full-text available
    The soft coral-derived fungus Trichoderma harzianum (XS-20090075) was found to be a potential strain to produce substantial new compounds in our previous study. In order to explore its potential to produce more metabolites, chemical epigenetic manipulation was used on this fungus to wake its sleeping genes, leading to the significant changes of its secondary metabolites by using a histone deacetylase (HDAC) inhibitor. The most obvious difference was the original main products harziane diterpenoids were changed into cyclonerane sesquiterpenoids. Three new terpenoids were isolated from the fungal culture treated with 10 μM sodium butyrate, including cleistanthane diterpenoid, harzianolic acid A (1), harziane diterpenoid, harzianone E (2), and cyclonerane sesquiterpenoid, 3,7,11-trihydroxy-cycloneran (3), together with 11 known sesquiterpenoids (4–14). The absolute configurations of 1–3 were determined by single-crystal X-ray diffraction, ECD and OR calculations, and biogenetic considerations. This was the first time to obtain cleistanthane diterpenoid and africane sesquiterpenoid from genus Trichoderma, and this was the first chlorinated cleistanthane diterpenoid. These results demonstrated that the chemical epigenetic manipulation should be an efficient technique for the discovery of new secondary metabolites from marine-derived fungi.
  • ... The prenylated indole alkaloids and prenylated aromatic compounds isolated from plants and microorganisms show broad structural diversity and various biological activities [1][2][3][4][5][6]. The prenylation may increase the lipophilicity and/ or binding ability to target protein that directly influences the biological activity [7,8]. ...
    Article
    Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for diversification of the natural products and improvement of the biological activities. For a decade, the characterization of enzymes and enzymatic synthesis of prenylated compounds by using ABBA-type and DMATS-type PTases have been demonstrated. Here, I introduce several examples of the studies on chemoenzymatic synthesis of unnatural prenylated compounds and the enzyme engineering of ABBA-type and DMATS-type PTases.
  • ... Interestingly, CBD exhibits strong antimicrobial properties against clinically relevant multidrug-resistant bacteria (MDR) such as the methicillinresistant Staphylococcus aureus (MRSA) strains, and the drug-resistant Mycobacterium tuberculosis XDR-TB with minimum inhibitory concentration (MIC) ranging from 0.5-2 μg/mL. These activities compare favourably with standard antibiotics for these strains [12]. Essential oils of cannabis showed moderate potency with an IC50 of 33 μg/mL against several yeasts, including Cryptococcus neoformans, Candida glabrata, and C. krusei [13]. ...
    Article
    Full-text available
    Plants, including cannabis (Cannabis sativa subsp. sativa), host distinct beneficial microbial communities on and inside their tissues and organs, including seeds. They contribute to plant growth, facilitating mineral nutrient uptake, inducing defence resistance against pathogens, and modulating the production of plant secondary metabolites. Understanding the microbial partnerships with cannabis has the potential to affect the agricultural practices by improving plant fitness and the yield of cannabinoids. Little is known about this beneficial cannabis-microbe partnership, and the complex relationship between the endogenous microbes associated with various tissues of the plant, and the role that cannabis may play in supporting or enhancing them. This review will consider cannabis microbiota studies and the effects of endophytes on the elicitation of secondary metabolite production in cannabis plants. The review aims to shed light on the importance of the cannabis microbiome and how cannabinoid compound concentrations can be stimulated through symbiotic and/or mutualistic relationships with endophytes.
  • ... Compounds 1-5 were evaluated for their antibacterial activities against three strains of pathogenic bacteria (Staphylococcus aureus, ATCC 25922, Escherichia coli ATCC 25923, Pseudomonas aeruginosa ATCC 27853) by using conventional broth dilution assay. 24 Ciprofloxacin was used as a positive control. ...
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    Full-text available
    One new terphenyl glycoside (1), gliocladinin D, together with 4 known compounds (2-5) were isolated from the sponge-derived fungus Trichoderma reesei (HN-2016-018). The structure of the new compound was elucidated by the comprehensive spectroscopic analysis, including 1-dimensional and 2-dimensional nuclear magnetic resonance, and high-resolution electrospray ionization mass spectrometry. Compound 3 exhibited moderate Topo I inhibitory activity.
  • ... Phenol is well known to have anti-pathogenic functions, which was of course championed by Joseph Lister as 'carbolic acid' to sterilise surgical instruments and wounds in the 19th century. In fact phenolcontaining molecules, such as the phytocannabinoids, display potent anti-microbial activity; structure-activity studies indeed show that the phenol moiety is important in determining these compounds antibacterial activity (Appendino et al., 2008). Certainly, other phenolic containing compounds, including salicylic acid and other non-steroidal anti-inflammatory compounds, show a wide spectrum of anti-bacterial activity, and are being investigated for use in conditions like bacterial endocarditis, urinary tract infections and diabetic foot infection (Ahmed et al., 2017;Akhter, Baqai, & Aziz, 2010;Kupferwasser et al., 1999;Schoergenhofer, Schwameis, Lagler, & Jilma, 2016). ...
    Article
    Full-text available
    Medicine has utilised plant‐based treatments for millennia, but precisely how they work is unclear. One approach is to use a thermodynamic viewpoint that life arose by dissipating geothermal and/or solar potential. Hence, the ability to dissipate energy to maintain homeostasis is a fundamental principle in all life, which can be viewed as an accretion system where layers of complexity have built upon core abiotic molecules. Many of these compounds are chromophoric and are now involved in multiple pathways. Plants have further evolved a plethora of chromophoric compounds that can not only act as sunscreens and redox modifiers, but also have now become integrated into a generalised stress adaptive system. This could be an extension of the dissipative process. In animals, many of these compounds are hormetic, modulating mitochondria and calcium signalling. They can also display anti‐pathogen effects. They could therefore modulate bioenergetics across all life due to the conserved electron transport chain and proton gradient. In this review paper, we focus on well‐described medicinal compounds, such as salicylic acid and cannabidiol and suggest, at least in animals, their activity reflects their evolved function in plants in relation to stress adaptation, which itself evolved to maintain dissipative homeostasis.
  • Preprint
    Full-text available
    The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate stationary phase cells persistent to antibiotics. We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.
  • Article
    Objective: Evaluate the effect of topical 1% cannabidiol on second intention wound healing in distal limb wounds of horses. Design: Experimental. Animals: Six Standardbred horses. Methods: A total of five 2.5 cm × 2.5 cm full thickness skin wounds were created on the dorsomedial aspect of the metacarpi of 6 horses. Wounds were contaminated with faeces on the day of wound creation. Each wound was then assigned to a treatment group; compounded 1% cannabidiol in unique manuka factor (UMF) 5 manuka honey, UMF 5 manuka honey, UMF 20 manuka honey or saline. Each treatment was applied topically daily for a total of 42 days. Legs were bandaged and bandages were changed, daily, for 13 days postoperatively. Digital photographs of each wound were taken on day 1 then weekly for 6 weeks. Wound size, daily healing rate and total time to healing were recorded and compared statistically. Results: Irrespective of the treatment, wounds did not retract as expected in the first 7 days after wound creation. There was no difference in wound area, daily healing rate, days to complete healing between treatment groups. Conclusions: This preliminary study failed to demonstrate any difference in wound healing variables between treatment groups in this model of second intention wound healing. This was unexpected due to the established effects of UMF 20 manuka honey on wound healing using the same model. This may be due to systemic effects of cannabidiol and study design. Further research into the use of cannabidiol in equine wounds is warranted.
  • Article
    Full-text available
    The chemical composition of the inflorescences from four Cannabis sativa L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and trans-cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of Cannabis sativa L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.
  • Thesis
    Full-text available
    The MPhil study presented in this thesis was an extension of a collaborative research partnership between the Indigenous Bioresources Research Group (IBRG) of Macquarie University and Chungtia village (Chungtia Senso Mokokchung Town, CSMT), Nagaland, for documentation of ethnobotanical knowledge of Chungtia village Elders and healers as well as phytochemical and biological activity investigation and isolation of bioactive constituents from Nagaland medicinal plants. The project was initiated by Meyanungsang Kichu, a Nagaland person, who conducted an ethnobotanical study of medicinal plants used by Chungtia villagers and documented 135 plants for their various ethnomedicinal and ethnobotanical applications. This MPhil study completed an up to date literature review of the 135 medicinal plants, then investigated the antimicrobial potential of those plants used by Chungtia villagers for skin conditions, conducted antimicrobial screening of a selection of these, and finally investigated in detail one plant for its antimicrobial activity and bioactive constituents. A comprehensive literature review covering traditional usages of all 135 plants by other Indigenous traditional healers’ worldwide and phytochemical and biological properties of these plants was conducted. This revealed that the traditional usages by the Chungtia community of 93 of their medicinal plants are in agreement with the uses of other Indigenous communities. Thirteen species were found to have no reports on their traditional uses, other than our first-hand accounts of the Chungtia community. Out of 93 species that were found to be used in a similar way by other communities, 80 had traditional uses that were consistent with pharmacological studies that have been reported in the literature and 55 of these plants had also had phytochemical studies conducted that showed bioactive compounds that aligned with their traditional uses by the Chungtia villagers. A detailed literature review was conducted on the antimicrobial properties and relevant phytoconstituents of 35 plants used by the Chungtia villagers for skin related conditions of a possible microbial origin. This highlighted twelve species with either no antimicrobial properties reported and/or no antimicrobial compounds identified. Out of these, seven species (Dendrocnide sinuata, Duabanga grandiflora, Erythrina stricta, Eurya acuminata, Holboellia latifolia, Maesa indica and Prunus persica) that were available for collection were selected for antimicrobial screening. The antimicrobial screening of the 70% aqueous ethanolic extracts of the plants (D. sinuate stem, D. grandiflora stem bark, E. stricta stem, E. acuminata leaves, H. latifolia leaves, M. indica leaves and P. persica roots) was performed using disc diffusion and MTT microdilution assays against the human pathogenic microorganisms Staphylococcus aureus (susceptible S. aureus), methicillin resistant S. aureus (MRSA) and multi drug resistant S. aureus (MDRSA), susceptible beta-lactamase negative Escherichia coli (β- E. coli), β- lactamase positive (antibiotic resistant) E. coli (β+ E. coli), Pseudomonas aeruginosa, Streptococcus pyogenes, Salmonella typhimurium and Candida albicans. The highest inhibitory activities were exhibited by the P. persica root extract, with MIC values of 156 μg/mL for all tested S. aureus strains. Based on the antibacterial screening results, P. persica was selected for further biological and chemical investigations for its antibacterial constituents. The 70% aqueous ethanolic P. persica roots extract was subjected to partitioning with different polarity solvents (n-hexane, dichloromethane, ethyl acetate). The most potent inhibitory activity was observed for the n-hexane and ethyl acetate partitions against susceptible and resistant strains of S. aureus. The GS-MS analysis of the n-hexane partition revealed the presence of eight constituents, out of which three were reported in the literature as antibacterial against S. aureus. TLC bioautographic methods reported in the literature were trialled with the aim to develop the most appropriate technique for the bioautography guided isolation process. The overlay method was found to be the most effective for the purpose of this study. TLC bioautography guided isolation by normal phase chromatography, size exclusion chromatography and preparative TLC led to the isolation of β-sitosterol (5.1) from the n-hexane partition and afzelechin (5.2) and ent-epiafzelechin-(2α→O→7’,4α→8’)-(-)-ent-afzelechin (5.3) from the ethyl acetate partition. The structures of these three compounds were determined based on various spectroscopic methods, including mass spectrometry, nuclear magnetic resonance spectroscopy, Infrared spectroscopy and circular dichroism. β-Sitosterol was found to be moderately active (MIC 1250 μg/mL) against P. aeruginosa as well as weakly active (MIC 2500 μg/mL) against susceptible strains of S. aureus, E. coli and S. typhimurium. ent-Epiafzelechin-(2α→O→7’,4α→8’)-(-)-ent-afzelechin showed good antibacterial activity against all the tested strains of S. aureus (MIC 156 μg/mL for susceptible and 312 μg/mL for resistant) as well as weak activity against the susceptible strains of E. coli, P. aeruginosa and S. typhimurium (MIC 2500 µg/mL, for all bacteria). This is the first report of this compound possessing antibacterial activity. The antimicrobial properties of afzelechin were not tested due to the small quantity of sample.
  • Thesis
    This PhD thesis is part of ongoing project to identify plant natural products and selected synthetic compounds that possess antimicrobial properties; and are able to promote plasmid loss or interfere with bacterial conjugation. The conjugative broad host plasmids investigated include PKM101 (Inc N), TP114 (Inc I2), PUB307 (Inc P), and low- copy number plasmids: R6K (Inc X), R7K (Inc W) and R1-drd-19 (Inc F11). They represented the incompatibility plasmid groups that are currently associated with gross dissemination of antibiotic resistance in bacteria. A series of plant extracts evaluated at sub-inhibitory concentration of 100 mg/L, were shown to inhibit bacterial plasmid conjugation and their active constituents were isolated and characterised. Mallotus philippinensis yielded rottlerin and red compound, with good to moderate antibacterial activity against multidrug resistant Staphylococcus aureus strains, and had a broad range inhibition against the resistant plasmids. Investigation of extracts from the resin of Cannabis sativa L. identified tetrahydrocannabinolic acid (THCA) and cannabinolic acid (CBNA) which in addition to two synthetic cannabinoids: cannabigerol and olivetol inhibited the conjugal transfer of TP114 between E. coli strains. The antiplasmid activities of Δ9-THC, CBN, CBD, significantly reduced the transfer of amoxicillin–resistance conferring PKM 101. Methanolic extract from the dried fruits of Evodia rutaecarpa yielded evodiamine, rutaecarpine and naturally-isolated sucrose. Rutaecarpine was the most active alkaloid against NorA-expressing SA1199B and XU212 strain expressing TetK efflux mechanism. Evodiamine and sucrose had lesser antibacterial effect as well as low level of inhibition against the plasmids. Rutaecarpine and evocarpine remarkably reduced the transfer frequency of PKM 101, showing a high 2 level effect of inhibition by the compound. The bioassay-guided analysis of Capsicum annuum L. yielded capsaicin and dihydrocapsaicin (DHC) which demonstrated moderate antibacterial activities but inhibited conjugal transfer of R-plasmids actively. Capsaicin exhibited a broad range antiplasmid activity while DHC showed selective inhibition. The effect of synthetic compounds that were assessed: ferulenol, 6-gingerol and 6-shogoal were twice as effective against the transfer of PKM 101, TP114 and PUB307 compared to capsaicin, while nonivamide had no remarkable activity. With the exception of promethazine, capsaicin and dihydrocapsaicin that showed some interaction with DNA due to decreased fluorescence which suggests binding, the rest of the compounds: rottlerin, red compound, ferulenol, evocarpine, rutaecarpine, 6-gingerol, 6-shogaol and nonivamide did not bind to DNA. This may indicate other probable mechanism of antiplasmid action of the compounds. Together, some of these compounds were notable for their dual properties: robust antistaphylococcal activity and a broad host range antiplasmid effect, and are reported for the very first time. Such potentials are valuable in the discovery of next generation antimicrobial drugs.
  • Article
    A new epimer of azaphilone derivative pinophilin B, epi-pinophilin B (1), and three known analogues (2–4) were obtained from the culture of the gorgonian-derived fungus Aspergillus fumigatus 14–27. The structures of 1–4, including their relative configurations were determined by extensive spectroscopic analysis and comparing with literature data. The absolute configuration of 1 was determined by electronic circular dichroism (ECD) and optical rotatory (OR) calculations methods. Compounds 1–4 were isolated from A. fumigatus for the first time. Their antibacterial and cytotoxic activities were also evaluated.
  • Article
    (‒)‐Cannabidiol ((‒)‐CBD), a non‐psychoactive phytocannabinoid from Cannabis, and its structural analogs have received growing attention in recent years because of their potential therapeutic benefits, including neuroprotective, anti‐epileptic, anti‐inflammatory, anxiolytic, anti‐cancer properties. (‒)‐CBD and its analogs have been obtained mainly based on the extraction from the natural source; however, the conventional extraction‐based methods have some drawbacks, such as poor quality control along with purification difficulty. Chemical‐synthetic strategies for (‒)‐CBD could tackle these issues, and, additionally, generate novel (‒)‐CBD analogs that exhibit advanced biological activities. This review concisely summarizes the historic and recent milestones in the synthetic strategies for (‒)‐CBD and its analogs.
  • Article
    The plant Sophora tonkinensis, possessed a range of active compounds, was traditionally used in the medicine of Chinese minorities. Endophytic fungi were isolated from this plant, of which the fungus Diaporthe sp. GDG-118 was fermented and extracted with methanol. The extract was screened by antifungal and antibacterial assays leading to the discovery of two new 21-acetoxycytochalasins (1-2) and five known cytochalasins (3-7). These two new compounds were elucidated by spectroscopic analyses, and further their absolute configurations were determined by the X-ray of compound 3 and comparing their experimental CD spectra. The antibacterial and antifungal effects of these compounds were evaluated. Compound 2 showed significant inhibitory activity against Bacillus anthraci and Escherichia coli with MIC value of 12.5 μg/mL, and 7 showed strong antifungal activity against Alternaria oleracea, Pestalotiopsis theae and Colletotrichum capsici with MIC values of 3.125, 1.56 and 1.56 μg/mL, respectively.
  • Article
    Full-text available
    The spread of antimicrobial resistance continues to be a priority health concern worldwide, necessitating exploration of alternative therapies. Cannabis sativa has long been known to contain antibacterial cannabinoids, but their potential to address antibiotic resistance has only been superficially investigated. Here, we show that cannabinoids exhibit antibacterial activity against MRSA, inhibit its ability to form biofilms and eradicate pre-formed biofilms and stationary phase cells persistent to antibiotics. We show that the mechanism of action of cannabigerol is through targeting the cytoplasmic membrane of Gram-positive bacteria and demonstrate in vivo efficacy of cannabigerol in a murine systemic infection model caused by MRSA. We also show that cannabinoids are effective against Gram-negative organisms whose outer membrane is permeabilized, where cannabigerol acts on the inner membrane. Finally, we demonstrate that cannabinoids work in combination with polymyxin B against multi-drug resistant Gram-negative pathogens, revealing the broad-spectrum therapeutic potential for cannabinoids.
  • Article
    A simple and efficient BPO-promoted free radical-based cascade reaction of biaryl vinyl ethers with easily available unactivated alkanes has been developed. A series of 6-alkyl 6H-benzo[c]chromenes have been successfully obtained...
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  • Article
    Boron trifluoride etherate on alumina catalyses the condensation of resorcinols an monomethyl resorcinols with several monoterpenoid allylic alcohols: in contrast to parallel reactions with boron trifluoride etherate in solution the products obtained do not undergo further cyclisations.
  • Article
    The minimum inhibiting concentrations (MIC) of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) for staphylococci and streptococci in broth are in the range of 1–5 μg/ml. In the same range, both compounds are also bactericidal. In media containing 4% serum or 5% blood the antibacterial activity is strongly reduced (MIC 50μg/ml). Gram-negative bacteria are resistant to THC and CBD.
  • Article
    Full-text available
    Als ein sedativer und antibiotisch wirksamer Bestandteil des deutschen Faserhanfes wird ein β-Resorcylsäure-Derivat diskutiert. Für die pharmakologische wie biologische Wirksamkeit wird auf die Fähigkeit zur Chelation hingewiesen.
  • Article
    Full-text available
    Chromatographic and spectroscopic data was determined for 16 different major cannabinoids from Cannabis sativa plant material as well as 2 human metabolites of Δ‐tetrahydrocannabinol. Spectroscopic analysis included UV absorbance, infrared‐spectral analysis, (GC‐) mass spectrometry, and spectrophotometric analysis. Also, the fluorescent properties of the cannabinoids are presented. Most of this data is available from literature but scattered over a large amount of scientific papers. In this case, analyses were carried out under standardised conditions for each tested cannabinoid so spectroscopic data can be directly compared. Different methods for the analysis of cannabis preparations were used and are discussed for their usefulness in the identification and determination of separate cannabinoids. Data on the retention of the cannabinoids in HPLC, GC, and TLC are presented.
  • Article
    The syntheses of (-)-cannabidiol and (-)-cannabidiol dimethyl ether were accomplished via fragmentation of an appropriately substituted 9-bromocamphor derivative. A new method of alpha-arylation of 3,9-dibromocamphor was shown to provide a variety of alpha-arylated camphor derivatives in good yields.
  • Article
    A total of 110 staphylococcal isolates from human skin were found to express a novel type of erythromycin resistance. The bacteria were resistant to 14-membered ring macrolides (MIC 32-128 mg/l) but were sensitive to 16-membered ring macrolides and lincosamides. Resistance to type B streptogramins was inducible by erythromycin. A similar phenotype, designated MS resistance, was previously described in clinical isolates of coagulase-negative staphylococci from the USA. In the UK, MS resistance is widely distributed in coagulase-negative staphylococci but was not detected in 100 erythromycin resistant clinical isolates of Staphylococcus aureus. Tests for susceptibility to a further 16 antibiotics failed to reveal any other selectable marker associated with the MS phenotype. Plasmid pattern analysis of 48 MS isolates showed considerable variability between strains and no common locus for the resistance determinant. In one strain of S. epidermidis co-resistance to tetracycline, penicillin and erythromycin (MS) was associated with a 31.5 kb plasmid, pUL5050 which replicated and expressed all three resistances when transformed into S. aureus RN4220. The MS resistance determinant was localised to a 1.9 kb fragment which was cloned on to the high-copy-number vector, pSK265. A constitutive mutant of S. aureus RN4220 containing the 1.9 kb fragment remained sensitive to clindamycin. This observation, together with the concentration-dependent induction (optimum 5 mg/l of erythromycin) of virginiamycin S resistance suggests that the MS phenotype is not due to altered expression of MLS resistance determinants (erm genes) but probably occurs via a different mechanism.
  • Article
    Some cannabispiro compounds and tetrahydrocannabidiolic acid were tested for antibacterial plasmid curing activity and inhibition of plasmid transfer. MIC values of the compound were above 1500 micrograms/ml. Cannabispirol and tetrahydrocannabidiolic acid eliminated the F'lac plasmid from Escherichia coli, but acetylcannabispirol, cannabispirone and cannabispirenone were ineffective as curing agents. Each compound, except acetyl-cannabispirol, selectively killed plasmid carrying bacteria. The compounds inhibited R144 plasmid transfer from E. coli into E. coli cells via inhibition of mating pair formation, zygotic killing and inhibition of transconjugal DNA synthesis in a lesser extent. All of the cannabispiro compounds and tetrahydrocannabidiolic acid inhibited the transformation with pBR322 plasmid DNA when the bacteria were pretreated with the compounds, via inhibition of the DNA penetration or decreasing the synthesis of plasmid DNA during bacterial growth. Although each of the compounds, except acetyl-cannabispirol, had a weak antibacterial effect which was more definite on plasmid carrying bacteria than plasmidless ones, and inhibited intercellular plasmid transfer and transforming activity of plasmid DNA, only two of them were able to cure F'lac plasmid showing that plasmid elimination is a complex process which strictly depends on the stereochemical configuration of curing agents.
  • Article
    Optically pure (-)-Δ1-THC (7) was produced in 50% yield (glc; isolated yield 31%) in a single-step synthesis from cis/trans-(+)-p-mentha-2,8-dien-1-ol (1) and olivetol (2) in the presence of 1% boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0°. The product was readily separated by column chromatography. The other major product formed was trans-Δ8-iso-THC (8). By the same procedure (-)-cannabidiol (3) was obtained on a preparative scale when <0.5% boron trifluoride etherate or wet p-toluene-sulfonic acid was used. A mechanistic scheme is presented for this reaction. It is shown that cannabidiols (3 and 4) are the key intermediates in this reaction and abnormal cannabidiol (4) undergoes a retro-Friedel-Crafts reaction followed by recombination to normal cannabidiol (3). This retroreaction of 4 is rationalized on steric arguments. The isolation and study of products from this reaction give a much clearer understanding of the factors which control the outcome of acid-catalyzed reactions of p-mentha-2,8-dien-1-ol and olivetol and have provided three new cannabinoids, 9, 10, and 12.
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    The methyl esters of cannabinolic, cannabidiolic and cannabigerolic acids are shown to possess structures, VIb, IVb and Ib respectively.
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    Cannabichromene homologs, analogs, and isomers as well as the C1-homolog and isomer of cannabigerol were prepared and tested for their antimicrobial and antifungal properties. Spectral data of all compounds synthesized are presented.
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    Cannabichromene (CBC) is one of four major cannabinoids in Cannabis sativa L. and is the second most abundant cannabinoid in drug-type cannabis. Cannabichromene and some of its homologs, analogs, and isomers were evaluated for antiinflammatory, antibacterial, and antifungal activity. Antiinflammatory activity was evaluated by the carrageenan-induced rat paw edema and the erythrocyte membrane stabilization method. In both tests, CBC was superior to phenylbutazone. Antibacterial activity of CBC and its isomers and homologs was evaluated using gram-positive, gram-negative, and acid-fast bacteria. Antifungal activity was evaluated using yeast-like and filamentous fungi and a dermatophyte. Antibacterial activity was strong, and the antifungal activity was mild to moderate.
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    An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) infection caused by a novel phage-type (now designated EMRSA-16) occurred in three hospitals in East Northamptonshire over a 21-month period (April 1991--December 1992). Four hundred patients were colonized or infected. Seven patients died as a direct result of infection. Chest infections were significantly associated with the outbreak strain when compared with methicillin-sensitive S. aureus. Twenty-seven staff and two relatives who cared for patients were also colonized. A 'search and destroy' strategy, as advocated in the current UK guidelines for control of epidemic MRSA was implemented after detection of the first case. Despite extensive screening of staff and patients and isolation of colonized and infected patients, the outbreak strain spread to all wards of the three hospitals except paediatrics and maternity. A high incidence of throat colonization (51%) was observed. Failure to recognize the importance of this until late in the outbreak contributed to the delay in containing its spread. Key parts of the strategy which eventually contained the local outbreak were the establishment of isolation wards in two hospitals, treatment of all colonized patients and staff to eradicate carriage and screening of all patients upon discharge from wards where MRSA had ever been detected. EMRSA-16 spread to neighbouring hospitals by early 1992 and to London and the South of England by 1993. It is distinguished from other epidemic strains by its characteristic phage-type, antibiogram (susceptibility to tetracycline and resistance to ciprofloxacin), and in the pattern given on pulse field electrophoresis.
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    A strain of methicillin-resistant Staphylococcus aureus (MRSA), EMRSA-15, was isolated in both the Midlands and south-east of England. This strain could be distinguished from another, very similar strain, found in the north of England, by both conventional and molecular typing. Conventional typing allowed distinction between the Midlands and southern variants of EMRSA-15, while molecular typing (pulse-field gel electrophoresis) allowed recognition of local variants in the south. In this investigation conventional and molecular typing methods were complementary.
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    Transport processes are used by all organisms to obtain essential nutrients and to expel wastes and other potentially harmful substances from cells. Such processes are important means by which resistance to selected antimicrobial agents in bacteria is achieved. The recently described Staphylococcus aureus norA gene encodes a membrane-associated protein that mediates active efflux of fluoroquinolones from cells. SA-1199B is a fluoroquinolone-resistant strain of S. aureus from which we cloned an allele of norA (norA1199). Similar to that of norA, the protein product of norA1199 preferentially mediates efflux of hydrophilic fluoroquinolones in both S. aureus and an Escherichia coli host, a process driven by the proton motive force. Determination of the nucleotide sequence of norA1199 revealed an encoded 388-amino-acid hydrophobic polypeptide 95% homologous with the norA-encoded protein. Significant homology with other proteins involved in transport processes also exists, but especially with tetracycline efflux proteins and with the Bacillus subtilis Bmr protein that mediates active efflux of structurally unrelated compounds, including fluoroquinolones. In S. aureus, the norA1199-encoded protein also appears to function as a multidrug efflux transporter. Southern hybridization studies indicated that norA1199 (or an allele of it) is a naturally occurring S. aureus gene and that related sequences are present in the S. epidermidis genome. The nucleotide sequence of the wild-type allele of norA1199, cloned from the fluoroquinolone-susceptible parent strain of SA-1199B, did not differ from that of norA1199 throughout the coding region. Northern (RNA) and Southern hybridization studies showed that increased transcription, and not gene amplification, of norA1199 is the basis for fluoroquinolone resistance in SA-1199B.
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    Fifty years of making analogs based on less than ten antibacterial scaffolds has resulted in the development and marketing of over 100 antibacterial agents but, with the exception of the oxazolidinone core, no new scaffolds have emerged in the past 30 years to address emerging resistance problems. As the support for antibacterial research shifts away from large pharmaceutical companies, a wave of biotechnology companies have pursued a diverse choice of targets resulting in several novel classes of agent in late-stage development. Although critical for certain resistance niche needs, these agents are unlikely to provide the solution to the requirement for a major novel scaffold class of antibacterials.
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    The occurrence of vancomycin-resistant Staphylococcus aureus (VRSA) and multidrug-resistant (MDR) strains of this organism necessitate the discovery of new classes of anti-staphylococcal drug leads. At present there a re no single chemical entity plant derived antibacterials used clinically, and this biologically diverse group deserves consideration as a source of chemical diversity for two important reasons. Firstly, plants have exceptional ability to produce cytotoxic agents and, secondly, there is an ecological rationale that antibacterial natural products Should be present or synthesised de novo following microbial attack to protect plants from invasive and pathogenic microbes in their environment. This review cites plant natural products that either modify resistance in Staphylococcus aureus or are antibacterial through bacteriostatic or bactericidal properties. The activities described here show that there are many potential new classes of anti-staphylococcal agents which Should undergo further cytotoxicity, microbial specificity and preclinical in vivo Studies to assess their potential.
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    Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.
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    The cannabis plant (Cannabis sativa L.) and products thereof (such as marijuana, hashish and hash oil) have a long history of use both as a medicinal agent and intoxicant. Over the last few years there have been an active debate regarding the medicinal aspects of cannabis. Currently cannabis products are classified as Schedule I drugs under the Drug Enforcement Administration (DEA) Controlled Substances act, which means that the drug is only available for human use as an investigational drug. In addition to the social aspects of the use of the drug and its abuse potential, the issue of approving it as a medicine is further complicated by the complexity of the chemical make up of the plant. This manuscript discusses the chemical constituents of the plant with particular emphasis on the cannabinoids as the class of compounds responsible for the drug's psychological properties.
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    The rapid spread of bacteria expressing multidrug resistance (MDR) has necessitated the discovery of new antibacterials and resistance-modifying agents. Since the initial discovery of bacterial efflux pumps in the 1980s, many have been characterized in community- and hospital-acquired Gram-positive and Gram-negative pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and, more recently, in mycobacteria. Efflux pumps are able to extrude structurally diverse compounds, including antibiotics used in a clinical setting; the latter are rendered therapeutically ineffective. Antibiotic resistance can develop rapidly through changes in the expression of efflux pumps, including changes to some antibiotics considered to be drugs of last resort. It is therefore imperative that new antibiotics, resistance-modifying agents and, more specifically, efflux pump inhibitors (EPIs) are characterized. The use of bacterial resistance modifiers such as EPIs could facilitate the re-introduction of therapeutically ineffective antibiotics back into clinical use such as ciprofloxacin and might even suppress the emergence of MDR strains. Here we review the literature on bacterial EPIs derived from natural sources, primarily those from plants. The resistance-modifying activities of many new chemical classes of EPIs warrant further studies to assess their potential as leads for clinical development.
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    Cannabinoids, the main constituents of the cannabis plant, are being increasingly studied for their medicinal properties. Cannabinolic acid (CBNA; 1) was synthesized from tetrahydrocannabinolic acid (THCA; 2), a major constituent of the cannabis plant, by aromatization using selenium dioxide mixed with trimethylsilyl polyphosphate as catalyst in chloroform. Purification was achieved by centrifugal partition chromatography, and the final product had a purity of over 96% by GC analysis. Spectroscopic data on CBNA such as 1H-NMR and IR, and molar extinction coefficients, as well as chromatographic data are presented as useful references for further research on CBNA. The developed method allows production of CBNA on a preparative scale, making it available for further studies on its biological activities as well as use as a reference standard for analytical procedures.
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    The phenolic diterpene totarol had good antimicrobial activity against effluxing strains of Staphylococcus aureus. Subinhibitory concentrations reduced the MICs of selected antibiotics, suggesting that it may also be an efflux pump inhibitor (EPI). A totarol-resistant mutant that overexpressed norA was created to separate antimicrobial from efflux inhibitory activity. Totarol reduced ethidium efflux from this strain by 50% at 15 μM (1/4× MIC), and combination studies revealed marked reductions in ethidium MICs. These data suggest that totarol is a NorA EPI as well as an antistaphylococcal antimicrobial agent.
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    Mupirocin resistance in Staphylococcus aureus is increasingly being reported in many parts of the world. This study describes the epidemiology and laboratory characterization of mupirocin-resistant methicillin-resistant S. aureus (MRSA) strains in Canadian hospitals. Broth microdilution susceptibility testing of 4,980 MRSA isolates obtained between 1995 and 2004 from 32 Canadian hospitals was done in accordance with CLSI guidelines. The clinical and epidemiologic characteristics of strains with high-level mupirocin resistance (HLMupr) were compared with those of mupirocin-susceptible (Mups) strains. MRSA strains were characterized by pulsed-field gel electrophoresis (PFGE) and typing of the staphylococcal chromosomal cassette mec. PCR was done to detect the presence of the mupA gene. For strains with mupA, plasmid DNA was extracted and subjected to Southern blot hybridization. A total of 198 (4.0%) HLMupr MRSA isolates were identified. The proportion of MRSA strains with HLMupr increased from 1.6% in the first 5 years of surveillance (1995 to 1999) to 7.0% from 2000 to 2004 (P < 0.001). Patients with HLMupr MRSA strains were more likely to have been aboriginal (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5 to 9.4; P = 0.006), to have had community-associated MRSA (OR, 2.2; 95% CI, 1.0 to 5.0; P = 0.05), and to have been colonized with MRSA (OR, 1.7; 95% CI, 1.0 to 3.0; P = 0.04). HLMupr MRSA strains were also more likely to be resistant to fusidic acid (21% versus 4% for mupirocin-susceptible strains; P < 0.001). All HLMupr MRSA strains had a plasmid-associated mupA gene, most often associated with a 9-kb HindIII fragment. PFGE typing and analysis of the plasmid profiles indicate that both plasmid transmission and the clonal spread of HLMupr MRSA have occurred in Canadian hospitals. These results indicate that the incidence of HLMupr is increasing among Canadian strains of MRSA and that HLMupr MRSA is recovered from patients with distinct clinical and epidemiologic characteristics compared to the characteristics of patents with Mups MRSA strains.
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    Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known hospital pathogen. More than 10% of bloodstream infections in hospitals are due to MRSA, and patients with MRSA have worse outcomes than those with methicillin-sensitive S aureus.1- 2 In recent years, identification of MRSA in otherwise healthy individuals in the community (community-associated MRSA) has become increasingly common.