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Evaluation of N-Phenyl-2-aminothiazoles for Treatment of Multi-Drug Resistant and Intracellular Staphylococcus aureus Infections
Abstract
The increasing emergence of antibiotic-resistant bacterial pathogens calls for additional urgency in the development of new antibacterial candidates. N-Phenyl-2-aminothiazoles are promising candidates that possess potent anti-MRSA activity and could potentially replenish the MRSA antibiotic pipeline. The initial screen of a series of compounds in this novel class against several bacterial strains revealed that the aminoguanidine analogues possessed promising activities and superior safety profiles. The determined MICs of these compounds were comparable to, if not better than, those of the control drugs (linezolid and vancomycin). Remarkably, compounds 3a, 3b, and 3e possessed potent activities against multidrug resistant staphylococcal isolates and several clinically important pathogens, such as vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. In addition, the compounds were superior to vancomycin in the rapid killing of MRSA and the longer post-antibiotic effects. Furthermore, low concentrations of compounds 3a, 3b, and 3e reduced the intracellular burden of MRSA by greater than 90%. Initial in vitro PK/toxicity assessments revealed that compound 3e was highly tolerable and possessed a low metabolic clearance rate and a highly acceptable half-life.
... In the studies reviewed, vancomycin was used at higher concentrations than can be expected in the bone but still showed a maximal inhibition effect of a 2-log reduction, independent of the cell type used. 17,74,125,141,144,162,163 It was possible to increase the effect in combination with other agents, such as ansamycins, 146 bacteriophages, 144 peptide-conjugated antimicrobial peptide TAT-KR12 164 or efflux pump inhibitors, 152 but not with liposomes or pegylated liposomes. 163 Interestingly, vancomycin showed increased antimicrobial potency when used after 7 days compared to that at an immediate treatment time. ...
... Even though the variety of dosages of the antibiotics used gives a broader insight into the effectiveness of the treatment, using concentrations multiple times higher than can be expected to be achieved in the bone could render findings less meaningful. The different antibiotic concentrations used can be related to the experimental approach employed, with some studies based on the actual measured MIC in vitro, 54,74,125,142,152,162 while others chose the concentrations based on the maximum plasma/ serum 17,74,75 or bone 53,135,153 concentrations observed in vivo. Ideally, both factors need to be considered. ...
... Some studies evaluated a treatment as being significantly effective when a certain percentage, e.g., 50% reduction, in the number of CFU was achieved, 55,57,58,142,153,157,165,178 while others considered the linear reduction in the CFU count, 126,141,156,163,179 logarithmic bacterial number reduction, 17,53,74,75,95,97,125,144,146,150,162,166 or only host-cell survival. 136 Since complete clearance is rarely achievable and a bacterial reduction of less than 1-log does not seem to be useful in an infection context, in this article, an effort was made to compare results at a logarithmic level. ...
Approximately 40% of treatments of chronic and recurrent osteomyelitis fail in part due to bacterial persistence. Staphylococcus aureus , the predominant pathogen in human osteomyelitis, is known to persist by phenotypic adaptation as small-colony variants (SCVs) and by formation of intracellular reservoirs, including those in major bone cell types, reducing susceptibility to antibiotics. Intracellular infections with S. aureus are difficult to treat; however, there are no evidence-based clinical guidelines addressing these infections in osteomyelitis. We conducted a systematic review of the literature to determine the demonstrated efficacy of all antibiotics against intracellular S. aureus relevant to osteomyelitis, including protein biosynthesis inhibitors (lincosamides, streptogramins, macrolides, oxazolidines, tetracyclines, fusidic acid, and aminoglycosides), enzyme inhibitors (fluoroquinolones and ansamycines), and cell wall inhibitors (beta-lactam inhibitors, glycopeptides, fosfomycin, and lipopeptides). The PubMed and Embase databases were screened for articles related to intracellular S. aureus infections that compared the effectiveness of multiple antibiotics or a single antibiotic together with another treatment, which resulted in 34 full-text articles fitting the inclusion criteria. The combined findings of these studies were largely inconclusive, most likely due to the plethora of methodologies utilized. Therefore, the reported findings in the context of the models employed and possible solutions for improved understanding are explored here. While rifampicin, oritavancin, linezolid, moxifloxacin and oxacillin were identified as the most effective potential intracellular treatments, the scientific evidence for these is still relatively weak. We advocate for more standardized research on determining the intracellular effectiveness of antibiotics in S. aureus osteomyelitis to improve treatments and patient outcomes.
... For the synthesis of 1,3-thiazoles by reacting thiosemicarbazide derivatives with various haloketones, very different reaction conditions are chosen, e.g., aprotic solvents are used [16,17] and protic [18,19] solvents are used. Also, the reactions are carried out with a base catalyst [20][21][22] or without a base catalyst [23][24][25]. ...
... In our previous works [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], 2-aminothiazoles and their derivatives were synthesized by the Hantzsch reaction, and some compounds showed promising antimicrobial activity. In the course of continuing research on the synthesis of 2-aminothiazole derivatives, several new fluorenyl-hydrazinthiazoles derivatives were synthesized and evaluated for their antimicrobial activity. ...
Fluorenyl-hydrazonothiazole derivatives 2–7 were synthesized by the Hantzsch reaction from 2-(9H-fluoren-9-ylidene)hydrazine-1-carbothioamide (1) and the corresponding α-halocarbonyl compounds in THF or 1,4-dioxane solvent. A base catalyst is not necessary for synthesising thiazoles, but it can shorten the reaction time. The antimicrobial properties of all synthesized compounds were screened for multidrug-resistant microorganism strains. The minimum inhibitory concentration of the tested compounds against Gram-positive bacteria and fungi was higher than 256 μg/mL, but several compounds had activity against Gram-positive strains.
... MBCs of 21 and 31 were determined by spotting the wells showing no growth onto BHIS agar plates. The MBC was categorized as the lowest concentration that reduced bacterial growth by 99.9% [59][60][61][62]. ...
... Cytotoxicity assessment for compounds 21 and 31 was determined against a human colorectal adenocarcinoma (Caco-2) cell line, as described previously [56,61,63]. Briefly, cells were incubated with the compounds (in triplicates) for 24 h. ...
The cytoplasmic steps of peptidoglycan synthesis represent an important targeted pathway for development of new antibiotics. Herein, we report the synthesis of novel 3-oxopyrazolidin-4-carboxamide derivatives with variable amide side chains as potential antibacterial agents targeting MurA enzyme, the first committed enzyme in these cytosolic steps. Compounds 15 (isoindoline-1,3-dione-5-yl), 16 (4-(1H-pyrazol-4-yl)phenyl), 20 (5-cyanothiazol-2-yl), 21 and 31 (5-nitrothiazol-2-yl derivatives) exhibited the most potent MurA inhibition, with IC 50 values of 9.8-12.2 μM. Compounds 15, 16 and 21 showed equipotent inhibition of the C115D MurA mutant developed by fosfomycin-resistant Escherichia coli. NMR binding studies revealed that some of the MurA residues targeted by 15 also interacted with fosfomycin, but not all, indicating an overlapping but not identical binding site. The antibacterial activity of the compounds against E. coli ΔtolC suggests that inhibition of MurA accounts for the observed effect on bacterial growth, considering that a few potent MurA inhibitors could not penetrate the bacterial outer membrane and were therefore inactive as proven by the bacterial cell uptake assay. The most promising compounds were also evaluated against a panel of Gram-positive bacteria. Remarkably, compounds 21 and 31 (MurA IC 50 = 9.8 and 10.2 μM respectively) exhibited a potent activity against Clostridioides difficile strains with MIC values ranging from 0.125 to 1 μg/mL, and were also shown to be bactericidal with MBC values between 0.25 and 1 μg/mL. Furthermore, both compounds were shown to have a limited activity against human normal intestinal flora and showed high safety towards human colon cells (Caco-2) in vitro. The thiolactone derivative (compound 5) exhibited an interesting broad spectrum antibacterial activity despite its weak MurA inhibition. Altogether, the presented series provides a promising class of antibiotics that merits further investigation.
... MBCs were determined by spotting the wells showed no growth onto tryptic soy agar (TSA) plates. The MBC was determined as the lowest concentration that resulted in 99.9% reduction in bacterial growth [55][56][57]. ...
... A multi-step resistance selection experiment as described elsewhere [57,64,65] was used to assess S. aureus ATCC 25923's ability to develop resistance against the alkynyl isoquinolines (HSN 584 and HSN 739), vancomycin and ciprofloxacin. MIC was determined daily over a course of 27 days using the broth microdilution method. ...
A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.
... The post-antibiotic effect (PAE) of AZM and EZM was tested against two N. gonorrhoeae strains (CDC 181, and CDC 186) following the procedure previously described [72][73][74] . Briefly, N. gonorrhoeae strains were grown in brucella supplemented broth to logarithmic phase and further diluted to reach an initial inoculum of about 1 Â 10 6 CFU/mL. ...
... The PAE is important data that, in combination with in vivo pharmacokinetics, can inform the proper dosing regimen 80,81 . PAE was determined as previously described 72,73,82 . AZM displayed an observed PAE ranging from 2 to 4 h against N. gonorrhoeae strains tested while EZM exhibited a long PAE of at least 10 h against all the strains tested (Table 4). ...
Neisseria gonorrhoeae is a high-priority pathogen of concern due to the growing prevalence of resistance development against approved antibiotics. Herein, we report the anti-gonococcal activity of ethoxzolamide, the FDA-approved human carbonic anhydrase inhibitor. Ethoxzolamide displayed an MIC50, against a panel of N. gonorrhoeae isolates, of 0.125 µg/mL, 16-fold more potent than acetazolamide, although both molecules exhibited almost similar potency against the gonococcal carbonic anhydrase enzyme (NgCA) in vitro. Acetazolamide displayed an inhibition constant (Ki) versus NgCA of 74 nM, while Ethoxzolamide’s Ki was estimated to 94 nM. Therefore, the increased anti-gonococcal potency of ethoxzolamide was attributed to its increased permeability in N. gonorrhoeae as compared to that of acetazolamide. Both drugs demonstrated bacteriostatic activity against N. gonorrhoeae, exhibited post-antibiotic effects up to 10 hours, and resistance was not observed against both. Taken together, these results indicate that acetazolamide and ethoxzolamide warrant further investigation for translation into effective anti-N. gonorrhoeae agents.
... A relatively smaller number of studies have described compounds targeted to the bacterial membrane and the formation and disruption of biofilm. Aminoguanidine derivatives have recently captured the attention of numerous researchers because of their diverse range of biological properties, including their antibacterial (compound A) 6 and anti-inflammatory (compound B) activities 7 . Eissa et al. reported that a new series of synthetic compounds bearing the aminoguanidine scaffold with potent antibacterial activity against MRSA and VRSA (compound C) 8 . ...
In an effort to identify novel antibacterial agents, we presented two series of aminoguanidine derivatives that were designed by incorporating 1,2,4-triazol moieties. All compounds exhibited strong in vitro antibacterial activity against a variety of testing strains. Compound 5f was identified as a potent antibacterial agent with a minimum inhibitory concentration (MIC) of 2–8 µg/mL against S. aureus, E. coli, S. epidermidis, B. subtilis, C. albicans, multi-drug resistant Staphylococcus aureus and multi-drug resistant Escherichia coli and low toxicity (Hela > 100 µM). Membrane permeability and transmission electron microscopy (TEM) image studies demonstrated that compound 5f permeabilized bacterial membranes, resulting in irregular cell morphology and the rapid death of bacteria. The results of the present study suggested that aminoguanidine derivatives with 1,2,4-triazol moieties were the intriguing scaffolds for the development of bactericidal agents.
... N-Phenyl-2-aminothiazole represents a core structure predicted to be a highly potent anti-MRSA agent and is expected to fill the arsenal against MRSA antibiotic resistance. Preliminary studies of a compound library based on these structural core aminoguanidine analogues 31a-e showed promising activity against different strains of bacteria and excellent safety profile (Fig. 10) [94]. Compounds 31a, 31b and 31e were active against MRSA with MICs between 2 and 4 μg/mL. ...
... For a long time, MRSA has been considered as an extracellular biofilm-forming parasite [61], but in the last decades multiple studies have reported its ability to shelter inside phagocytic and non-phagocytic cells (Figure 2A) [65,66]. MRSA's ability to occupy an intracellular niche significantly increases pathogen survival under therapy with multiple antibiotics, including methicillin, cephalosporins, macrolides, aminoglycosides, and others [65,67,68]. To date, the most commonly used treatment strategy involves intravenous vancomycin administration. ...
Metal-organic frameworks (MOFs) are a highly versatile class of ordered porous materials, which hold great promise for different biomedical applications, including antibacterial therapy. In light of the antibacterial effects, these nanomaterials can be attractive for several reasons. First, MOFs exhibit a high loading capacity for numerous antibacterial drugs, including antibiotics, photosensitizers, and/or photothermal molecules. The inherent micro- or meso-porosity of MOF structures enables their use as nanocarriers for simultaneous encapsulation of multiple drugs resulting in a combined therapeutic effect. In addition to being encapsulated into an MOF’s pores, antibacterial agents can sometimes be directly incorporated into an MOF skeleton as organic linkers. Next, MOFs contain coordinated metal ions in their structure. Incorporation of Fe2/3+, Cu2+, Zn2+, Co2+, and Ag+ can significantly increase the innate cytotoxicity of these materials for bacteria and cause a synergistic effect. Finally, abundance of functional groups enables modifying the external surface of MOF particles with stealth coating and ligand moieties for improved drug delivery. To date, there are a number of MOF-based nanomedicines available for the treatment of bacterial infections. This review is focused on biomedical consideration of MOF nano-formulations designed for the therapy of intracellular infections such as Staphylococcus aureus, Mycobacterium tuberculosis, and Chlamydia trachomatis. Increasing knowledge about the ability of MOF nanoparticles to accumulate in a pathogen intracellular niche in the host cells provides an excellent opportunity to use MOF-based nanomedicines for the eradication of persistent infections. Here, we discuss advantages and current limitations of MOFs, their clinical significance, and their prospects for the treatment of the mentioned infections.
... The antibacterial activity of the benzimidazole compounds was evaluated using the broth microdilution method as outlined previously [67][68][69][70]. Briefly, a 0.5 McFarland standard solution from each strain was prepared and diluted in cation-adjusted Mueller-Hinton broth to reach a concentration of ~5 × 10 5 CFU/mL. ...
Antibiotic-resistant bacteria represent a serious threat to modern medicine and human life. Only a minority of antibacterial agents are active against Gram-negative bacteria. Hence, the development of novel antimicrobial agents will always be a vital need. In an effort to discover new therapeutics against Gram-negative bacteria, we previously reported a structure-activity-relationship (SAR) study on 1,2-disubstituted benzimidazole derivatives. Compound III showed a potent activity against tolC-mutant Escherichia coli with an MIC value of 2 μg/mL, representing a promising lead for further optimization. Building upon this study, herein, 49 novel benzimidazole compounds were synthesized to investigate their antibacterial activity against Gram-negative bacteria. Our design focused on three main goals, to address the low permeability of our compounds and improve their cellular accumulation, to expand the SAR study to the unexplored ring C, and to optimize the lead compound (III) by modification of the methanesulfonamide moiety. Compounds (25a-d, 25f-h, 25k, 25l, 25p, 25r, 25s, and 26b) exhibited potent activity against tolC-mutant E. coli with MIC values ranging from 0.125 to 4 μg/mL, with compound 25d displaying the highest potency among the tested compounds with an MIC value of 0.125 μg/mL. As its predecessor, III, compound 25d exhibited an excellent safety profile without any significant cytotoxicity to mammalian cells. Time-kill kinetics assay indicated that 25d exhibited a bacteriostatic activity and significantly reduced E. coli JW55031 burden as compared to DMSO. Additionally, combination of 25d with colistin partially restored its antibacterial activity against Gram-negative bacterial strains (MIC values ranging from 4 to 16 μg/mL against E. coli BW25113, K. pneumoniae, A. baumannii, and P. aeruginosa). Furthermore, formulation of III and 25d as lipidic nanoparticles (nanocapsules) resulted in moderate enhancement of their antibacterial activity against Gram-negative bacterial strains (A. Baumannii, N. gonorrhoeae) and compound 25d demonstrated superior activity to the lead compound III. These findings establish compound 25d as a promising candidate for treatment of Gram-negative bacterial infections and emphasize the potential of nano-formulations in overcoming poor cellular accumulation in Gram-negative bacteria where further optimization and investigation are warranted to improve the potency and broaden the spectrum of our compounds.
... MRSA (methicillin-resistant Staphylococcus aureus) is a form of S. aureus that is resistant to the antibiotic methicillin and other medications such as penicillin, amoxicillin, and oxacillin [6]. There are several drug resistance mechanisms in MRSA, including cell wall thickening, enhanced efflux pumps over the cell membrane, mutation of drug targets in the cytoplasm, modification of drug, and transformation in the colonization status of the bacteria [3,[7][8][9]. These mechanisms allow S. aureus to survive in various groups of antibiotics, consisting of fluoroquinolones, β-lactamases, glycol-peptides, and aminoglycosides [10]. ...
Antibiotics, which are crucial to treat or prevent bacterial infections, are compounds used to kill or slow down the growth of bacteria. In recent years, antibiotic resistance has grown into a serious medical concern, so the application of antibiotics in a controlled and targeted manner has shown excellent performance in overcoming this challenge. Towards this goal, future research must be given priority to developing new functional materials for antibiotic delivery. Metal-organic frameworks (MOFs) with remarkable functionality, high biocompatibility, crystalline structure, and high porosity have recently shown their potential as bio-carriers. UiO-66, a zirconium and terephthalic acid-based MOF, with notable chemical and physical specialties such as high stability and potential biocompatibility, has attracted much attention in drug delivery. Herein, we develop a drug delivery mechanism using UiO-66-NH2 nanoparticles that is able to load and release the antibiotic Cefazolin (CEF) over several days. The characterization and structural elucidation of nanoparticles were evaluated by BET, XRD, TGA, SEM, FT-IR, TEM, Size, Zeta potential and adsorption kinetics, and the in vitro release rate of CEF from UiO-66 and UiO-66-NH2 showed promising results. Drug release results revealed 64.42 % and 78.88 % rate of CEF release over three days at pH 7 for UiO-66 and UiO-66-NH2, respectively. According to N2 adsorption-desorption isotherms at 77 K, the BET surface area for UiO-66-NH2 was smaller than that of UiO-66, which is attributed to the presence of the -NH2 group. The result of XRD pattern of UiO-66-NH2 showed a peak at 20.25° attributed to existence of –NH2 on the surface of UiO-66. Also, the XRD pecks of CEF-loaded into UiO-66-NH2 indicated a peak at 28.33° was observed related to CEF. The obtained data for TGA analysis showed that UiO-66 and UiO-66-NH2 based MOFs exhibit a stability up to 400°C after completely removing the solvent molecules (water and DMF) in the activation step. Additionally, the UiO-66-NH2 formulations showed relatively higher stability than UiO-66. Moreover, antimicrobial and antibiofilm assays were performed to assess such properties of CEF-loaded nanoparticles. The results of the broth microdilution method exhibited reduced MIC and MBC values of nanoparticles containing CEF compared to free CEF due to increased antimicrobial effect. It was also found that CEF-loaded nanoparticles have stronger antibiofilm activity than the free form of CEF, according to the results of anti-biofilm activity assays. In vitro characterization of UiO-66 and UiO-66-NH2 indicated the non-toxicity of the nanoparticles. Finally, by using the mouse incision wound model, UiO-66 and UiO-66-NH2 demonstrated promising wound healing properties. Overall, the CEF-loaded UiO-66-NH2 nanoparticles developed in this study can be considered as novel and advanced antibiotic delivery nanosystems with promising antibacterial and antibiofilm potentials both in vitro and in vivo.
... The best results of this method were obtained when the carbonyl compounds were refluxed with thiourea derivatives in ethanol in the presence of the catalyst to produce 20 (Scheme 12) [35]. In 2020, the base-promoted cyclisation of compound 21 with phenacyl bromide in tetrahydrofuran produced the thiazole derivative 22 (Scheme 13) [36]. ...
The thiazole scaffold is an essential structural foundation in a plethora of pharmaceutical products having an extensive array of biological activities. Consequently, its synthesis has been extensively discussed in the literature. In this mini review, we have summarized the recent advances of thiazole synthesis covering articles published between 2002 and 2021. We have reviewed and discussed variable recent and novel routes for the synthesis of compounds containing thiazole ring from various starting materials such as thiourea, thioamide or thiosemicarbazone. Additionally, we have illustrated environmentally benign methods for thiazole synthesis. We hope that this review can help other researchers in efficient synthesis of thiazole ring.
... MICs of diphenylureas were determined against staphylococcal clinical isolates using the broth microdilution method as described previously [50,51]. Briefly, a 0.5 McFarland standard bacterial solution was prepared and diluted in cation-adjusted Mueller-Hinton broth to achieve a bacterial concentration of about 5 Â 10 5 CFU/mL and seeded in 96-well plates. ...
A set of structurally related diphenylurea derivatives bearing aminoguanidine moiety were synthesized, and their antibacterial activity was assessed against a panel of multi-drug resistant Gram-positive clinical isolates. Two compounds 6 and 24 were identified with better bacteriological profile than the lead compound I. The multi-step resistance development studies indicated that MRSA are less likely to develop resistance toward diphenylurea compounds. Moreover, these compounds demonstrated a prolonged post-antibiotic effect than that of vancomycin. Furthermore, compounds 6 and 24 were able to re-sensitize VRSA to vancomycin, resulting in 8- to more than 32-fold improvement in vancomycin MIC values against clinical VRSA isolates. Finally, when assessed in an in vivo skin infection mouse model, the efficacy of compound 24 was very comparable to that of the commercially available fusidic acid ointment. Additionally, the diphenylurea 24 did not have a pronounced effect on the animal weights along the experiment indicating its safety and tolerability to mice. Taken together, these results indicate that the diphenylurea scaffold merits further investigation as a promising anti-staphylococcal treatment option.
... S. aureus is a clinically important bacterial species, which is effectively treated using the antibiotic vancomycin (Shahin et al., 2020;Simon et al., 2020). However, with the continuous use of antibiotics, vancomycin-resistant S. aureus strains are increasingly developing that can adapt to antibiotic environments and show strong phenotypic plasticity (Bakri et al., 2007). ...
Phenotypic plasticity is the exhibition of various phenotypic traits produced by a single genotype in response to environmental changes, enabling organisms to adapt to environmental changes by maintaining growth and reproduction. Despite its significance in evolutionary studies, we still know little about the genetic control of phenotypic plasticity. In this study, we designed and conducted a genome-wide association study (GWAS) to reveal genetic architecture of how Staphylococcus aureus strains respond to increasing concentrations of vancomycin (0, 2, 4, and 6 μg/mL) in a time course. We implemented functional mapping, a dynamic model for genetic mapping using longitudinal data, to map specific loci that mediate the growth trajectories of abundance of vancomycin-exposed S. aureus strains. 78 significant single nucleotide polymorphisms were identified following analysis of the whole growth and development process, and seven genes might play a pivotal role in governing phenotypic plasticity to the pressure of vancomycin. These seven genes, SAOUHSC_00020 ( walR ), SAOUHSC_00176, SAOUHSC_00544 ( sdrC ), SAOUHSC_02998, SAOUHSC_00025, SAOUHSC_00169, and SAOUHSC_02023, were found to help S. aureus regulate antibiotic pressure. Our dynamic gene mapping technique provides a tool for dissecting the phenotypic plasticity mechanisms of S. aureus under vancomycin pressure, emphasizing the feasibility and potential of functional mapping in the study of bacterial phenotypic plasticity.
... It has been demonstrated that MRSA has developed multiple drug-resistant mechanisms, including the thickening of cell wall, the increase of efflux pumps on cell membrane, the mutation of cytoplasmic drug targets, the modification of drugs and the change of bacterial colonization state [5,6]. These mechanisms ensure its great viability in the presence of many types of antibiotics, including b-lactam antibiotics, aminoglycosides, glycol-peptides and fluoroquinolones [7]. Thus, the treatment of MRSA infection is difficult and challenging, and it is of great importance to develop novel anti-MRSA approaches. ...
Abuse of antibiotics has led to the emergence of drug-resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) was reported just two years after the clinical use of methicillin, which can cause severe infections with high morbidity and mortality in both community and hospital. The treatment of MRSA infection is greatly challenging since it has developed the resistance to almost all types of antibiotics. As such, it is of great significance and importance to develop novel therapeutic approaches. The fast development of nanotechnology provides a promising solution to this dilemma. Functional nanomaterials and nanoparticles can act either as drug carriers or as antibacterial agents for antibacterial therapy. Herein, we aim to provide a comprehensive understanding of the drug resistance mechanisms of MRSA and discuss the potential applications of some functionalized nanomaterials in anti-MRSA therapy. Also, the concerns and possible solutions for the nanomaterials-based anti-MRSA therapy are discussed.
Increasing molecular flexibility improves the performance of thiazole aminoguanidines against drug-resistant bacteria and Gram-negative bacteria.
The combination of antibacterial and antiviral agents is becoming a very important aspect of dealing with resistant bacterial and viral infections. The N ‐phenylthiazole scaffold was found to possess significant anti‐MRSA, antifungal, and anti‐COVID‐19 activities as previously published; hence, a slight refinement was proposed to attach various alkyne lipophilic tails to this promising scaffold, to investigate their effects on the antimicrobial activity of the newly synthesized compounds and to provide a valuable structure–activity relationship. Phenylthiazole 4 m exhibited the most potent anti‐MRSA activity with 8 μg/mL MIC value. Compounds 4 k and 4 m demonstrated potent activity against Clostridium difficile with MIC values of 2 μg/mL and moderate activity against Candida albicans with MIC value of 4 μg/mL. When analyzed for their anti‐COVID‐19 inhibitory effect, compound 4 b emerged with IC 50 =1269 nM and the highest selectivity of 138.86 and this was supported by its binding score of −5.21 kcal mol ⁻¹ when docked against SARS‐CoV‐2 M pro . Two H‐bonds were formed, one with His164 and the other with Met49 stabilizing phenylthiazole derivative 4 b , inside the binding pocket. Additionally, it created two arene‐H bonds with Asn142 and Glu166, through the phenylthiazole scaffold and one arene‐H bond with Leu141 via the phenyl ring of the lipophilic tail.
In recent years, the overuse of antibiotics has resulted in the emergence of antibiotic resistance, which is a serious global health problem. Methicillin-resistant Staphylococcus aureus (MRSA) is a common and virulent bacterium in clinical practice. Numerous researchers have focused on developing new candidate drugs that are effective, less toxic, and can overcome MRSA resistance. Thiazole derivatives have been found to exhibit antibacterial activity against drug-sensitive and drug-resistant pathogens. By hybridizing thiazole with other antibacterial pharmacophores, it is possible to obtain more effective antibacterial candidate drugs. Thiazole derivatives have shown potential in developing new drugs that can overcome drug resistance, reduce toxicity, and improve pharmacokinetic characteristics. This article reviews the recent progress of thiazole compounds as potential antibacterial compounds and examines the structure-activity relationship (SAR) in various directions. It covers articles published from 2018 to 2023, providing a comprehensive platform to plan and develop new thiazole-based small MRSA growth inhibitors with minimal side effects.
With the continuous and alarming threat of exhausting the current antimicrobial arsenals, efforts are urgently needed to develop new effective ones. In this study, the antibacterial efficacy of a set of structurally related acetylenic-diphenylurea derivatives carrying the aminoguanidine moiety was tested against a panel of multidrug-resistant Gram-positive clinical isolates. Compound 18 was identified with a superior bacteriological profile than the lead compound I. Compound 18 demonstrated an excellent antibacterial profile in vitro: low MIC values, extended post-antibiotic effect, refractory ability to resistance development upon extended repeated exposure, and high tolerability towards mammalian cells. Finally, when assessed in a MRSA skin infection animal model, compound 18 showed considerable healing and less inflammation, decrease in the bacterial loads in skin lesions, and it surpassed fusidic acid in controlling the systemic dissemination of S. aureus. Collectively, compound 18 represents a promising lead anti-MRSA agent that merits further investigation for the development of new anti-staphylococcal therapeutics.
Antimicrobial resistance is an aggravating global issue therefore it has been under extensive research in an attempt to reduce the number of antibiotics that are constantly reported as obsolete jeopardizing the lives of millions worldwide. Thiazoles possess a reputation as one of the most diverse biologically active nuclei, and phenylthiazoles are no less exceptional with an assorted array of biological activities such as anthelmintic, insecticidal, antimicrobial, antibacterial, and antifungal activity [1]. Recently phenyl thiazoles came under the spotlight as a scaffold having strong potential as an anti-MRSA lead compound. It is a prominent pharmacophore in designing and synthesizing new compounds with antibacterial activity against multidrug-resistant bacteria such as MRSA, which is categorized as a serious threat pathogen, that exhibited concomitant resistance to most of the first-line antibiotics. MRSA has been associated with soft tissue and skin infections resulting in high death rates, rapid dissemination, and loss of millions of dollars of additional health care costs [2]. In this brief review, we have focused on the advances of phenylthiazole derivatives as potential anti-MRSA from 2014 to 2021. The review encompasses the effect on biological activity due to combining this molecule with various synthetic pharmacophores. The physicochemical aspects were correlated with the pharmacokinetic properties of the reviewed compounds to reach a structure-activity relationship profile. A summary of antibacterial activity of phenylthiazole derivatives against MRSA was added in a tabular form (Table 1). Lead optimization of phenyl thiazole derivatives has additionally been outlined where the lipophilicity of the compounds was balanced with the metabolic stability and oral solubility to aid the researchers in medicinal chemistry, design, and synthesizing effective anti-MRSA phenylthiazoles in the future.
A novel and facile metal-free method for the green synthesis of 2-amino-4-arylthiazole derivatives through the three-component cascade reaction of aromatic methyl ketones, elemental sulfur and cyanamide is reported. One C-N bond and two C-S bonds were formed in one-pot protocol without using catalysts.
Staphylococcus aureus is a serious threat to public health. S. aureus infection can cause acute or long-term persistent infections that are often resistant to antibiotics and are associated with high morbidity and death. Understanding the defensive systems of S. aureus can help clinicians make the best use of antimicrobial drugs and can also help with antimicrobial stewardship. The mechanisms and clinical implications of S. aureus defense systems, as well as potential response systems, were discussed in this study. Because resistance to all currently available antibiotics is unavoidable, new medicines are always being developed. Alternative techniques, such as anti-virulence and bacteriophage therapies, are being researched and may become major tools in the fight against staphylococcal infections in the future, in addition to the development of new small compounds that affect cell viability.
A novel class of 7-thiazoxime quinolones was developed as potential antimicrobial agents for the sake of bypassing resistance of quinolones. Biological assays revealed that some constructed 7-thiazoxime quinolones possessed effective antibacterial efficiency. Methyl acetate oxime derivative 6l exhibited 32-fold more active than ciprofloxacin against MRSA, which also possessed rapidly bactericidal ability and low toxicity towards mammalian cells. The combination use of 7-thiazoxime quinolone 6l and ciprofloxacin was able to improve antibacterial potency and effectively alleviate bacterial resistance. The preliminarily mechanism exploration revealed that compound 6l could destroy the cell membrane and insert into MRSA DNA to bind with DNA gyrase, then decrease the expression of gyrB and femB genes. The above results strongly suggested that methyl acetate oxime derivative 6l held a promise for combating MRSA infection.
Amines (2) and (26) were obtained from the condensation of the corresponding amines with 3,4-difluoronitrobenzene. The reduction of nitro group produced the corresponding amines (3 and 27). The synthesis of esters (7, 12, 19, 28) was carried out from the treatment of the amines, (1, 3, 18, 27) with ethyl bromoacetate, then these compounds were converted to the corresponding hydrazides (8, 13, 29) by the treatment with hydrazine hydrate. The triazole was obtained from the intramolecular cyclisation of the corresponding carbothioamide in basic media and this compound was then converted to the morpholine-triazole-penicillin hybrid by a mannich reaction. The cyclocondensation of hydrazine carbothioamides (9b, 14, 21) or urea (4) with 2-bromo-1-(4-chlorophenyl)ethenone generated the thiazole derivatives. On the other hand, the treatment of 4, 9b, and 14 with ethyl bromoacetate yielded 4-oxo-1,3-thiazolidines (6, 11, 16). Three methods containing conventional, microwave, and ultrasound-mediated techniques were applied. Best results were assessed using microwave-and ultrasound-promoted procedures. The structures of the newly synthesised compounds were elucidated by spectroscopic techniques, and the antimicrobial activity screening studies were also performed. Some of them exhibited good to moderate activity on the test bacteria.
Infections account for a major cause of death throughout the developing world. This is mainly due to the emergence of newer infectious agents and more specifically due to the appearance of antimicrobial resistance. With time, the bacteria have become smarter and along with it, massive imprudent usage of antibiotics in clinical practice has resulted in resistance of bacteria to antimicrobial agents. The antimicrobial resistance is recognized as a major problem in the treatment of microbial infections. The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Determination of bacterial resistance to antibiotics of all classes (phenotypes) and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis) are helpful. Better understanding of the mechanisms of antibiotic resistance will help clinicians regarding usage of antibiotics in different situations. This review discusses the mechanism of action and resistance development in commonly used antimicrobials.
The worldwide epidemic of antibiotic resistance is in danger of ending the golden age of antibiotic therapy. Resistance impacts on all areas of medicine, and is making successful empirical therapy much more difficult to achieve. Staphylococcus aureus demonstrates a unique ability to quickly respond to each new antibiotic with the development of a resistance mechanism, starting with penicillin, until the most recent, linezolid and daptomycin. Methicillin resistant S. aureus (MRSA) has become endemic today in hospitals worldwide. Resistance to the newer antimicrobial-agents - linezolid, vancomycin, teicoplanin, and daptomycin are been reported and also the fear of pandrug-resistance. This study was carried out to know the antimicrobial resistant pattern of MRSA to newer antibiotic, to know any isolates are extensively-drug resistant (XDR)/pandrug resistant (PDR), inducible macrolide-lincosamide streptogramin B (iMLSB), and mupirocin resistance. Thirty-six MRSA isolates resistant to the routinely tested antibiotic were further tested for list of antibiotic by a group of international experts. Isolates were tested for iMLSB and mupirocin resistance by the disk diffusion method. Of 385 MRSA, 36 (9.35%) isolates of MRSA were resistant to the routinely tested antibiotic. Among these 36 MRSA isolates, none of our isolates were XDR/PDR or showed resistant to anti-MRSA cephalosporins (ceftaroline), phosphonic acids, glycopeptides, glycylcyclines, and fucidanes. Lower resistance was seen in oxazolidinones (2.78%), streptogramins (5.56%), lipopeptide (5.56%). Thirty-four (94.44%) isolates showed constitutive MLSB (cMLSB) resistance and two (5.56%) iMLSB phenotypes. High- and low-level mupirocin resistance were seen in 13 (36.11%) and six (16.67%), respectively. In our study, none of our isolates were XDR or PDR. No resistance was observed to ceftaroline, telavancin, teicoplanin, and vancomycin; but the presence of linezolid resistance (1, 2.28%) and daptomycin resistance (2, 5.56%) in our rural set-up is a cause of concern.
Nosocomial infections are also known as hospital-acquired/associated infections. National
Healthcare Safety Network along with Centers for Disease Control for surveillance has
classified nosocomial infection sites into 13 types with 50 infection sites, which are specific
on the basis of biological and clinical criteria. The agents that are usually involved in hospitalacquired
infections include Streptococcus spp., Acinetobacter spp., enterococci, Pseudomonas
aeruginosa, coagulase-negative staphylococci, Staphylococcus aureus, Bacillus cereus,
Legionella and Enterobacteriaceae family members, namely, Proteus mirablis, Klebsiella
pneumonia, Escherichia coli, Serratia marcescens. Nosocomial pathogens can be transmitted
through person to person, environment or contaminated water and food, infected individuals,
contaminated healthcare personnel’s skin or contact via shared items and surfaces. Mainly,
multi-drug-resistant nosocomial organisms include methicillin-resistant Staphylococcus aureus,
vancomycin-resistant enterococci, Pseudomonas aeruginosa and Klebsiella pneumonia,
whereas Clostridium difficile shows natural resistance. Excessive and improper use of broadspectrum
antibiotics, especially in healthcare settings, is elevating nosocomial infections, which
not only becomes a big health care problem but also causes great economic and production loss
in the community. Nosocomial infections can be controlled by measuring and comparing the
infection rates within healthcare settings and sticking to the best healthcare practices. Centers
for Disease Control and Prevention provides the methodology for surveillance of nosocomial
infections along with investigation of major outbreaks. By means of this surveillance, hospitals
can devise a strategy comprising of infection control practices.
Staphylococcus aureus is a major human and veterinary pathogen worldwide. Methicillin-resistant S. aureus (MRSA) poses a significant and enduring problem to the treatment of infection by such strains. Resistance is usually conferred by the acquisition of a nonnative gene encoding a penicillin-binding protein (PBP2a), with significantly lower affinity for β-lactams. This resistance allows cell-wall biosynthesis, the target of β-lactams, to continue even in the presence of typically inhibitory concentrations of antibiotic. PBP2a is encoded by the mecA gene, which is carried on a distinct mobile genetic element (SCCmec), the expression of which is controlled through a proteolytic signal transduction pathway comprising a sensor protein (MecR1) and a repressor (MecI). Many of the molecular and biochemical mechanisms underlying methicillin resistance in S. aureus have been elucidated, including regulatory events and the structure of key proteins. Here we review recent advances in this area.
Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.
The postantibiotic effect (PAE) of tomopenem was determined after a 2 h exposure of two strains of meticillin-susceptible and meticillin-resistant Staphylococcus aureus (MSSA and MRSA), and imipenem-susceptible and imipenem-resistant Pseudomonas aeruginosa, to tenfold the respective MIC. The PAEs on MSSA and P. aeruginosa were approximately 1 h and they were comparable to those of meropenem. The PAE on MRSA was 1.5 to 3 h, equal to or longer than those of vancomycin. The PAEs of tomopenem not only were found for MRSA, but also were present in the imipenem-resistant P. aeruginosa tested.
Although nosocomial infections by Staphylococcus epidermidis have gained much attention, this skin-colonizing bacterium has apparently evolved not to cause disease, but to maintain the commonly benign relationship with its host. Accordingly, S. epidermidis does not produce aggressive virulence determinants. Rather, factors that normally sustain the commensal lifestyle of S. epidermidis seem to give rise to additional benefits during infection. Furthermore, we are beginning to comprehend the roles of S. epidermidis in balancing the epithelial microflora and serving as a reservoir of resistance genes. In this Review, I discuss the molecular basis of the commensal and infectious lifestyles of S. epidermidis.
Infectious disease caused by methicillin-resistant Staphylococcus aureus (MRSA) often develops in compromised hosts in whom a single administration of vancomycin is usually not effective. We assessed the combined antimicrobial effects of vancomycin and imipenem against MRSA growth in vitro as well as in vivo using a neutropenic mouse thigh infection model. Synergic and additive effects of the two drugs were observed for 34 and two, respectively, of the 36 clinical isolates of MRSA, as determined by the chequerboard method. For MRSA strain N, postantibiotic effect (PAE) values obtained in vitro were 1.9-2.6 h for vancomycin and 2.6-3.5 h for imipenem, while higher values of 2.7-4.4 h were obtained for the combination of vancomycin and imipenem. In vivo, a single administration of vancomycin at 1 or 2 mg/kg or of imipenem/cilastatin at 5 mg/kg produced growth curves similar to those in controls, with a suppressive time of 0 h. Imipenem/cilastatin at 10 mg/kg demonstrated a suppressive time of 3.1 h. Combinations of vancomycin 1 mg/kg plus imipenem/cilastatin 5 mg/kg, vancomycin 1 mg/kg plus imipenem/cilastatin 10 mg/k and vancomycin 2 mg/kg plus imipenem/cilastatin 10 mg/kg demonstrated suppressive times of 2.9, 3.9 and 5.2 h, respectively, indicating that combined administration was effective. Simultaneous administration of the two drugs was more effective than sequential administration. Thus, combined administration of vancomycin and imipenem/cilastatin proved effective for MRSA in vivo. The combined effects seemed to be synergic, since a single administration of either drug did not show anti-MRSA effects at the doses used in the combined regimen.
Bacterial resistance to antibiotics is presently one of the most pressing healthcare challenges and necessitates discovering new antibacterials with unique chemical scaffolds. However, determining the optimal balance between structural requirements for pharmacological action and pharmacokinetic properties of novel antibacterial compounds is a significant challenge in drug development. The incorporation of lipophilic moieties within a compound’s core structure can enhance biological activity but have a deleterious effect on drug-like properties. In this article, the lipophilicity of alkynylphenylthiazoles, previously identified as novel antibacterial agents, was reduced by introducing cyclic amines to the lipophilic side chain. In this regard, substitution with methylpiperidine (compounds 14-16) and thiomorpholine (compound 19) substituents significantly enhanced the aqueous solubility profile of the new compounds more than 150-fold compared to the first-generation lead compound 1b. Consequently, the pharmacokinetic profile of compound 15 was significantly enhanced with a notable improvement both in half-life and the time the compound’s plasma concentration remained above its minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA). In addition, compounds 14-16 and 19 were found to exert a bactericidal mode of action against MRSA and were not susceptible to resistance formation after 14 serial passages. Moreover, these compounds (at 2 × MIC) were superior to the antibiotic vancomycin in disrupting mature MRSA biofilm. The modifications to the alkynylphenylthiazoles reported herein successfully improved the pharmacokinetic profile of this new series while maintaining the compounds’ biological activity against MRSA.
Compounds with high lipophilic properties are often associated with bad physicochemical properties, triggering many off-targets, and less likely to pass clinical trials. Two metabolically stable phenylthiazole antibiotic scaffolds having notable high lipophilic characters, one with alkoxy side chain and the other one with alkynyl moiety, were derivatized by inserting a cyclic amine at the lipophilic tail with the objective of improving physicochemical properties and the overall pharmacokinetic behavior. Only alkynyl derivatives with 4- or 5-membered rings showed remarkable antibacterial activity. The azetidine-containing compound 8 was the most effective and it revealed a potent antibacterial effect against 15 multi-drug resistant (MDR)-Gram positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, Staphylococcus epidermidis and enterococci. Compound 8 was also highly effective in clearing 99.7% of the intracellular methicillin-resistant S. aureus (MRSA) harbored inside macrophages. In addition to the remarkable enhancement in aqueous solubility, the in vivo pharmacokinetic study in rats indicated that compound 8 can penetrate gut cells and reach plasma at a therapeutic concentration within 15 min and maintain effective plasma concentration for around 12 h. Interestingly, the main potential metabolite (compound 9) was also active as an antibacterial agent with potent antibiofilm activity.
A novel series of phenylthiazoles bearing cyclic amines at the phenyl-4 position was prepared with the objective of decreasing lipophilicity and improving the overall physicochemical properties and pharmacokinetic profile of the compounds. Briefly, the piperidine ring (compounds 10 and 12) provided the best ring size in terms of antibacterial activity when tested against 16 multidrug-resistant clinical isolates. Both compounds were superior to vancomycin in the ability to eliminate methicillin-resistant Staphylococcus aureus (MRSA), residing within infected macrophages and to disrupt mature MRSA biofilm. Additionally, compounds 10 and 12 exhibited a fast-bactericidal mode of action in vitro. Furthermore, the new derivatives were 160-times more soluble in water than the previous lead compound 1b. Consequently, compound 10 was orally bioavailable with a highly-acceptable pharmacokinetic profile in vivo that exhibited a half-life of 4 h and achieved a maximum plasma concentration that exceeded the minimum inhibitory concentration (MIC) values against all tested bacterial isolates.
The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing the central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against MDR-Gram-positive clinical isolates, including vancomycin- and linezolid-resistant MRSA, with a minimum inhibitory concentration (MIC) value as low as 0.5 g/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae and E. coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2× the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 hours suggesting a once-daily dosing regimen
Antibiotic resistance remains a pressing medical challenge for which novel antibacterial agents are urgently needed. The phenylthiazole scaffold represents a promising platform to develop novel antibacterial agents for drug-resistant infections. However, enhancing the physicochemical profile of this class of compounds remains a challenging endeavor to address to successfully translate these molecules into novel antibacterial agents in the clinic. We extended our understanding of the SAR of the phenylthiazoles’ lipophilic moiety by exploring its ability to accommodate a hydrophilic group or a smaller sized hetero-ring with the objective of enhancing the physicochemical properties of this class of novel antimicrobials. Overall, the 2-thienyl derivative 20 and the hydroxyl-containing derivative 31 emerged as the most promising antibacterial agents inhibiting growth of drug-resistant Staphylococcus aureus at a concentration as low as 1 μg/mL. Remarkably, compound 20 suppressed bacterial undecaprenyl pyrophosphatase (UppP), the molecular target of the phenylthiazole compounds, in a sub nano-molar concentration range (almost 20,000 times more potent than the lead compounds 1a and 1b). Compound 31 possessed the most balanced antibacterial and physicochemical profile. The compound exhibited rapid bactericidal activity against S. aureus, and successfully cleared intracellular S. aureus within infected macrophages. Furthermore, insertion of the hydroxyl group enhanced the aqueous solubility of 31 by more than 50-fold relative to the first-generation lead 1c.
Thirty-two new naphthylthiazole derivatives were synthesized with the aim of exploring their antimicrobial effect on multidrug-resistant Gram-positive bacteria. Compounds 25 and 32, with ethylenediamine and methylguanidine side chains, represent the most promising derivatives, as their antibacterial spectrum includes activity against multidrug-resistant staphylococcal and enterococcal strains. Moreover, the new derivatives are highly advantageous over the existing frontline therapeutics for the treatment of multidrug-resistant Gram-positive bacteria. In this vein, compound 25 possesses three attributes: no bacterial resistance was developed against it even after 15 passages, it was very efficient in targeting intracellular pathogens, and it exhibited a concentration-dependent ability to disrupt the preformed bacterial biofilm.
A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 6 h.
Enterococci are commensal microorganisms present in the gastrointestinal (GI) tract of humans. Though normally innocuous to the host, strains of Enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study confirms that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant E. faecium (minimum inhibitory concentration ranges from 1 to 8 µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in vitro results, and niclosamide's limited permeability across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction mice model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the feces, cecal content, and ileal content of infected mice after only eight days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the intestinal tract of mice. The results obtained indicate niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections.
A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin-and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.
A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis.
The success of Staphylococcus aureus as a pathogen is partly attributable to its ability to thwart host innate immune responses, which includes resisting the antimicrobial functions of phagocytes. Here, we have studied the interaction of methicillin-resistant S. aureus (MRSA) strain USA300 with murine RAW 264.7 and primary human macrophages using molecular imaging and single cell analysis to obtain an unprecedented understanding of the interaction between the macrophage and MRSA. Herein we demonstrate that macrophages fail to control intracellular infection by MRSA USA300 despite trafficking the bacteria into mature phagolysosomes. Using fluorescence-based proliferation assays we also show that intracellular staphylococci proliferate and that replication commences while the bacteria are residing in mature phagolysosomes hours after initial phagocytosis. Finally, live-cell fluorescence video microscopy allowed for unprecedented visual insight into the escape of MRSA from macrophages, demonstrating that the macrophages die through a pathway characterized by membrane blebbing and activation of caspase-3 followed by acquisition of the vital dye propidium iodide. Moreover, cell death precedes the emergence of MRSA from infected macrophages and these events can be ablated by prolonged exposure of infected phagocytes to gentamicin. This article is protected by copyright. All rights reserved.
Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA) infections are growing global health concerns. Structure-activity-relationships of phenylthiazoles as a new antimicrobial class have been addressed. We present 10 thiazole derivatives that exhibit strong activity against 18 clinical strains of MRSA and VRSA with acceptable PK profile. Three derivatives revealed an advantage over vancomycin by rapidly eliminating MRSA growth within six hours and no derivatives are toxic to HeLa cells at a concentration of 11 µg/mL.
Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.
Two novel series of hybrid class 4-chlorophenylthiazole-s-triazine were synthesized via nucleophilic substitution of 2,4,6-trichloro-1,3,5-triazine with distinguished alkenyl/alkyl/aryl/hetero alkyl-aryl amino and mercapto nucleophiles under nitrogen atmosphere. We identified that the spectrums of antibacterial activity of all tested compounds reveal promising and significant inhibition of gram-positive and gram-negative micro-organisms and the most active compounds, 31d and 32d, were found to be non-toxic in preliminary cytotoxicity assay. We also report that the Molinspiration and Osiris Property Explorer calculations have found a new lead 32d, which binds preferentially to the nuclear receptor to exhibit antibacterial potency.
Clin Microbiol Infect 2010; 16: 1721–1728
Methicillin-resistant Staphylococcus aureus (MRSA) clones have caused a huge worldwide epidemic of hospital-acquired infections over the past 20–30 years and continue to evolve, including the advent of virulent community strains. The burden on healthcare services is highly significant, in particular because MRSA has not replaced susceptible staphylococcal infection but is an additional problem. Treatment strategies for MRSA are suboptimal and compromise the care of patients. MRSA is associated with serious morbidity and mortality, both within and without hospitals. Although the literature on the costs of MRSA and its control is suboptimal, it is clear that the control of MRSA is highly desirable and likely to be cost-effective. Any compromises in control are likely to be false economies.
Staphylococcus aureus is the leading cause of bacterial infections in developed countries and produces a wide spectrum of diseases, ranging from minor skin infections to fatal necrotizing pneumonia. Although S. aureus infections were historically treatable with common antibiotics, emergence of drug-resistant organisms is now a major concern. Methicillin-resistant S. aureus (MRSA) was endemic in hospitals by the late 1960s, but it appeared rapidly and unexpectedly in communities in the 1990s and is now prevalent worldwide. This Review focuses on progress made toward understanding the success of community-associated MRSA as a human pathogen, with an emphasis on genome-wide approaches and virulence determinants.
The post-antibiotic effect (PAE) may allow for more widely spaced dosing of antibiotics than is currently employed without loss of efficacy. Antimicrobial combinations are widely used in clinical medicine. However, dosing schedules are usually based on pharmacological profiles of the drugs used alone. Previously we have demonstrated significant prolongation of the PAE induced by antimicrobial combinations in vitro as compared to PAEs induced by the agents alone. We examined this issue further in vivo in a neutropenic mouse thigh infection model, by exposing Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae to several antimicrobials, either singly or in combination. The PAE in vivo was defined as the difference in time needed for the organisms in the treated animals to grow 1 log10 as compared with controls after serum drug concentrations had fallen below the MIC. Drug concentrations exceeded the MIC for 1.2-3.2 h, but bactericidal activity occurred mainly during the first hour. When the agents were used singly a negative PAE was produced by ceftazidime against P. aeruginosa, a PAE of approximately 0 h by imipenem against E. coli and K. pneumoniae, a PAE of 2-4 h by cefazolin against S. aureus, gentamicin against E. coli and K. pneumoniae, and imipenem and tobramycin against P. aeruginosa, and a PAE of 6-7 h by gentamicin against S. aureus and rifampicin against P. aeruginosa. The beta-lactam/aminoglycoside combinations when used against S. aureus and P. aeruginosa prolonged the PAE by 1.0-3.3 h, compared with the longer of the individual drug PAEs, but no prolongation was observed against E. coli and K. pneumoniae. Ceftazidime reduced the PAE when used with tobramycin against P. aeruginosa. The long PAE of rifampicin against P. aeruginosa was 'carried over' to the combination, thus prolonging the growth suppression achieved by imipenem and tobramycin alone or in combination by 5.5-8.0 h. This effect on the PAE was additive only, and synergy was not observed. In conclusion, a potentially significant prolongation of the PAE by combination of drugs was observed in vivo, but only if both (or all) agents induced a PAE when used alone. The impact of this observation needs to be examined further in studies involving multiple and different dosing regimens in an infection model.
Bacteria that attach to surfaces aggregate in a hydrated polymeric matrix of their own synthesis to form biofilms. Formation
of these sessile communities and their inherent resistance to antimicrobial agents are at the root of many persistent and
chronic bacterial infections. Studies of biofilms have revealed differentiated, structured groups of cells with community
properties. Recent advances in our understanding of the genetic and molecular basis of bacterial community behavior point
to therapeutic targets that may provide a means for the control of biofilm infections.
The new oxazolidinone antimicrobial, linezolid, has been approved for the treatment of infections caused by various gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Although instances of linezolid resistance in VRE have been reported, resistance has not been encountered among clinical isolates of S aureus. We have characterised an MRSA isolate resistant to linezolid that was recovered from a patient treated with this agent for dialysis-associated peritonitis.
To investigate the antibacterial efficacy of vancomycin towards Staphylococcus aureus under aerobic and anaerobic conditions, and to assess the influence of oxygen on the duration of the post-antibiotic effect (PAE) after exposure to vancomycin.
Culture-based techniques and flow cytometric measurements of 5-cyano-2,3-ditolyl tetrazolium chloride (an indicator of redox activity) and the membrane potential-sensitive fluorophore Sytox Green, were used to test four staphylococcal strains. The MICs for all strains, and the duration of PAE, were similar whether tested with or without oxygen. However, a fivefold logarithmic reduction in cell counts was observed in 10-15 h aerobically, depending on strain, compared with longer than 60 h in an anaerobic environment. Flow cytometric data correlated well with counts of colony-forming units under both aerobic and anaerobic conditions.
The death rate of Staph. aureus exposed to vancomycin was greater in the presence of oxygen, although MIC values and PAE durations were similar whether tested aerobically or anaerobically. Also, flow cytometry provided a rapid and sensitive alternative to plate counts for the assessment of antibiotics in oxygen-free conditions.
This study underlines the need for further anaerobic testing using different strain/antibiotic combinations, the results of which will have clinical significance due to the anaerobic nature of some sites of infection.
For most countries badly affected by methicillin-resistant Staphylococcus aureus (MRSA) there have been many years of debate about its relative virulence compared with methicillin-susceptible S. aureus (MSSA) and whether it could be controlled. Now that it is endemic in the majority of hospitals around the world, it is clear that it is at least as virulent as MSSA and is an additional burden of healthcare-acquired infection. There is increasing evidence that, despite this endemicity, control efforts can be successful, although they are often perceived as expensive. In reality, there is a large body of consistent evidence that control is highly cost effective, particularly in the context of the huge societal costs of MRSA and the future ever-greater threats that it poses.
Green synthesis and characterization of some 4-substituted-N-aryl-1, 3-thiazole-2-amine derivative
- Mahajan
Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia
- Wunderink