Schematic representation of biological functions of bacterial efflux pumps. Efflux pumps play an important role in (a) efflux of antibiotics, (b) biofilm formation, (c) regulation of host physiology, (d) metal resistance, and (e) virulence.

Schematic representation of biological functions of bacterial efflux pumps. Efflux pumps play an important role in (a) efflux of antibiotics, (b) biofilm formation, (c) regulation of host physiology, (d) metal resistance, and (e) virulence.

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The problem of antibiotic resistance among pathogenic bacteria has reached a crisis level. The treatment options against infections caused by multiple drug-resistant bacteria are shrinking gradually. The current pace of the discovery of new antibacterial entities is lagging behind the rate of development of new resistance. Efflux pumps play a centr...

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... transport proteins localized in the cytoplasmic membrane of bacteria that actively translocate the chemical across the membrane. Efflux pumps are involved in the regulation of the internal environment by extruding out the toxic substances, quorum sensing molecules (autoinducers), biofilm formation molecules, and virulence factors of the bacteria (Fig. 2) [12]. Efflux pumps can confer heavy metal resistance by exporting metal ions such as Ag 2+ , Cu 2+ , Co 2+ , Zn 2+ , Cd 2+ and Ni 2+ . In Gram-negative bacteria, efflux pumps help to reduce not only the cytoplasmic concentration of heavy metal ions but also the periplasmic concentration; since periplasmic metal ions can re-enter the ...

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... Efflux pumps are a major mechanism by which bacteria expel antibiotics, rendering many drugs ineffective [65]. By inhibiting these pumps, the extract increases the intracellular concentration of antibiotics like tetracycline, potentially restoring their efficacy [66]. The optimized extract was shown to increase the accumulation of EtBr in the MDR A. baumannii cells over time, suggesting the inhibition of efflux pump activity. ...
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The rising incidence of multidrug-resistant (MDR) Acinetobacter baumannii infections underscores the urgent need for novel antimicrobial strategies. The aim of this study was to investigate the synergistic effects between a polyphenol-rich extract from Phyllanthus emblica fruit and tetracycline against MDR A. baumannii strains. The extraction process was optimized using the Box-Behnken design approach to maximize the total phenolic content (TPC) of the P. emblica extract. Key variables, including ethanol concentration, extraction time, and solid-to-liquid ratio (w/v), were determined through single-factor experiments. The antimicrobial activity of the extract, both alone and in combination with tetracycline, was evaluated against A. baumannii. Mechanistic studies focusing on bacterial lysis and efflux pump inhibition were conducted to assess the extract's effects and its combined potential with tetracycline. The Box-Behnken design successfully optimized the extraction conditions, yielding the highest TPC at 68.92% ethanol concentration, 1.85 days of extraction time, and a 1:9.58 w/v ratio. The predicted and experimentally verified TPC values of the extract were 129.19 and 130.76±2.46 mg GAE/g samples, respectively, with no significant difference (p>0.05). The extract contained several phenolic compounds identified using liquid chromatography–high-resolution mass spectrometry (LC-HRMS). It exhibited antimicrobial activity against MDR Acinetobacter baumannii, either alone or in combination with tetracycline. The combination demonstrated a synergistic effect against MDR A. baumannii, with a fractional inhibitory concentration index (FICI) of 0.37. Moreover, the combination showed superior bacteriolytic effects against MDR A. baumannii cells, as evidenced by increased release of nucleic acid components and membrane destabilization, compared to the extract or tetracycline alone (p<0.0001 for all comparisons). Additionally, the combination significantly enhanced the efflux pump inhibition effect compared to the extract or tetracycline alone (p<0.05 for both). These findings support the potential use of polyphenol-rich P. emblica extracts as adjuncts to conventional antibiotics in treating drug-resistant bacterial infections.
... Another mechanism in drug resistance is the expression of efflux pumps, whose activity decreases the intracellular concentration of drugs by expelling antibiotics. Also, these pumps remove other substances harmful to bacteria such as metals, disinfectants, or dyes (Figure 2) [10]. In this chapter, we will review the impact of efflux pumps expressed by mycobacteria in developing multidrug resistance, which largely contributed to the resurgence of this disease and its declaration as a global health emergency by the World Health Organization [3]. ...
... MmpL transporters are classified into two groups based on structural motifs. Group I comprises MmpL1, 2,4,5,5,6,7,8,9,10, and 12 and has a distinguishable predicted docking domain in the periplasmic loop region. Group II comprises MmpL3, 11, and the fusion protein MmpL13a/b [34]. ...
... Untapped natural products can be a valuable resource for potential efflux pump inhibitors. Additionally, machine learning can help us to screen new efflux pump inhibitors [10]. ...
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Mycobacteria, including nontuberculous mycobacteria (NTM) and Mycobacterium tuberculosis complex (MTB), are global pathogens of major concern due to their intrinsic drug resistance and their capacity to cause a wide range of severe infections. The treatment of mycobacterial infections is particularly challenging because of the multidrug resistance. Efflux pumps are involved in drug resistance by actively expelling antibiotics. A promising strategy to decrease drug resistance is the inhibition of efflux pump activity by efflux pump inhibitors. In this chapter, we will review the current knowledge on efflux pumps and their impact on clinical drug resistance, as well as the potential of efflux pump inhibitors to mitigate resistance. The search for novel compounds as efflux pump inhibitors or the inclusion of existing inhibitors in the current drug therapy for mycobacterial infections has become a major goal in the treatment of these diseases.
... This resistance is likely mediated by specific ARGs identified in the genome, including those associated with efflux pumps, such as acrA, acrAB-TolC, CRP, and rsmA. These genes are known to contribute to multidrug resistance by actively expelling antibiotics from bacterial cells, thereby lowering intracellular drug concentrations and diminishing their effectiveness (Gaurav et al., 2023;Weston et al., 2018). Moreover, the presence of the msbA which is associated with resistance to nitroimidazole antibiotics is unique in M. phragmitis PSU-3885-11 among the studied Mangrovibacter strains (Alfaray et al., 2023). ...
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Mangrovibacter phragmitis is a Gram-negative bacterium typically found in plant roots that supports nitrogen fixation in nutrient-poor environments such as mangrove ecosystems. Although primarily found in environmental niches, an unusual case in Thailand of M. phragmitis strain PSU-3885–11 isolated from the sputum of a 29-year-old female patient with spinal tuberculosis. This isolate was initially misidentified as part of the Enterobacter cloacae complex (ECC) by MALDI-TOF. However, WGS subsequently confirmed its correct identity as M. phragmitis. The genome contains 4,651 coding sequences, along with 72 tRNA genes and 1 tmRNA. Moreover, comparative genomic analysis showed 99.32 % average nucleotide identity (ANI) similar to M. phragmitis MP23, and several antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) were identified in the PSU-3885–11 genome which may contribute to its ability to survive in diverse environments, including human hosts. The PSU-3885–11 displayed resistance to beta-lactam antibiotics such as ampicillin and cefotaxime, while remaining sensitive to a wide range of other antibiotics. Key virulence genes including ompA, hcp/tssD, and rpoS, were identified which may play a role in its persistence in human hosts as an opportunistic pathogen. The presence of ribosomally synthesized and post-translationally modified peptides (RiPPs) and bacteriocins indicates the antimicrobial properties that may provide a competitive advantage in both environmental and clinical settings of this strain. Therefore, this study provides valuable insights into the genomic features, antibiotic resistance, and potential pathogenicity of M. phragmitis PSU-3885–11. The findings also emphasize the importance of continued surveillance and genomic analysis of environmental bacteria that may emerge as opportunistic pathogens in human infections.
... Mechanistic studies of elaiophylin suggest it may act as an effective inhibitor of bacterial efflux pumps, a highly promising target for overcoming bacterial resistance [57]. Efflux pump inhibitors, when used in combination with antibiotics, enhance the efficacy of these drugs by blocking active efflux mechanisms, making resistant bacteria more susceptible [58]. Beyond antimicrobial activity, members of the elaiophylin family have also been noted for their anti-cancer [59], antimalarial [60], and immunomodulatory properties [61], suggesting that elaiophylin may hold therapeutic potential beyond its bactericidal effects. ...
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Background: The increasing prevalence of drug-resistant tuberculosis (TB) underscores the urgent need for novel antimicrobial agents. Methods: This study integrates cultivation optimization, nuclear magnetic resonance (NMR) fingerprinting, and principal component analysis (PCA) to explore microbial secondary metabolites as potential anti-TB agents. Results: Using the combined approach, 11 bioactive compounds were isolated and identified, all exhibiting anti-Mycobacterium bovis BCG activity. Notable findings include borrelidin, a potent threonyl-tRNA synthetase inhibitor with broad biological activities, and L-O-Lac-L-Val-D-O-Hiv-D-Val, a peptide isolated for the first time from a plant endophyte, demonstrating broad-spectrum antimicrobial activity. Additionally, elaiophylin and polycyclic tetramate macrolactams (PTMs) displayed significant bactericidal effects, with elaiophylin achieving complete BCG inhibition at 72 h and PTMs marking their first reported anti-TB activity. The study also identified bafilomycins as potent scaffolds for anti-TB drug development, showcasing rapid bactericidal activity at low MIC values. Conclusion: These findings emphasize the value of microbial metabolites as a reservoir of bioactive compounds and provide new avenues for developing next-generation anti-TB therapies.
... Lebih lanjut, Escherichia coli dapat mengembangkan mekanisme resistensi yang dapat mengurangi efektivitas antimikroba dari minyak zaitun. Hal ini sejalan dengan penelitian Gaurav et al. (2023), bahwa bakteri dapat mengembangkan mekanisme resistensi salah satunya aktivasi pompa effluks. Pompa efluks merupakan protein transpor yang terletak di membran sitoplasma dan terlibat dalam pengaturan intraseluler bakteri. ...
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Penelitian ini bertujuan untuk mengevaluasi efek antimikroba dari tiga jenis minyak zaitun—extra virgin olive oil, extra light olive oil, dan olive pomace oil—terhadap pertumbuhan bakteri Escherichia coli. Resistensi antibiotik yang meningkat, terutama terhadap bakteri gram negatif seperti E. coli, telah menjadi masalah kesehatan global. Minyak zaitun, yang kaya akan senyawa fenolik, diharapkan dapat menjadi alternatif alami untuk mengatasi masalah ini. Penelitian ini menggunakan metode disc diffusion untuk mengukur zona hambat dari masing-masing minyak zaitun terhadap E. coli yang diinokulasi pada media MacConkey Agar. Hasil menunjukkan bahwa ketiga jenis minyak zaitun tidak memiliki aktivitas antimikroba yang signifikan, dengan rata-rata zona hambat masing-masing 6,6 mm untuk extra virgin olive oil, 6,5 mm untuk extra light olive oil, dan 6,5 mm untuk olive pomace oil. Uji statistik Kruskal-Wallis dan Mann-Whitney menunjukkan tidak ada perbedaan signifikan antara kelompok perlakuan. Temuan ini mengindikasikan bahwa E. coli resisten terhadap senyawa antimikroba dalam minyak zaitun.
... In recent years, it has been reported that bacterial multidrug resistance is partially dependent on the active exocytosis of drugs; that is, exocytosis proteins or regulatory proteins are induced by antimicrobial drugs and expel the drugs, resulting in low intracellular drug concentration [16,17]. Multidrug efflux pumps are membrane proteins and can be categorized into six different families [18][19][20], including ATP-binding cassette (ABC) transporter, resistance nodulation division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), small multidrug resistance (SMR), and proteobacterial antimicrobial compound efflux (PACE) [21]. The RND family has clinical significance because it confers endogenous resistance to Gram-negative bacteria and the associated infections are more difficult to treat [22,23]. ...
... Heterologous expression of the efflux pump SrpABC in Escherichia coli improves tolerance to n-butanol [27]. The EmrAB-TolC belongs to MFS which is the largest and most diverse superfamily of secondary transporters, which not only play a crucial role in the transport of many substances but are also closely related to immunological issues such as viral invasion and bacterial resistance [20,28,29]. Porins constitute a significant proportion of outer membrane proteins within Enterobacteriaceae. ...
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Phenolic compounds are industrially versatile chemicals that have been successfully produced in microbial cell factories. Unfortunately, most phenolic compounds are highly toxic to cells in specific cellular environments or above a particular concentration because they form a complex with iron and promote hydroxyl radical production in Fenton reactions, resulting in the ferroptosis of cells. Here, we demonstrated that overexpression of efflux pumps and porins, including porins LamB and OmpN, and efflux pumps EmrAB, MdtABC, and SrpB, can enhance Escherichia coli phloroglucinol (PG) tolerance by inhibiting the generation of hydroxyl radicals. In addition, LamB and OmpN overexpression improved the bioproduction of PG. Furthermore, efflux pumps and porins can enhance bacterial tolerance to various phenolic compounds, including phenol, catechol, resorcinol, pyrogallol, and 2-naphthol. LamB and MdtABC confer a generalized tolerance to phenols. However, EmrAB, OmpN, and SrpB showed inconsistent effects of bacterial tolerance to different phenolic compounds. Our results will theoretically support the construction of phenolic compound-tolerant bacteria strains, which should be more efficient in the biosynthesis of phenols.
... Recent studies [27,28] have suggested that efflux pump mechanisms play a crucial role in bacterial responses to metal ions by regulating intracellular concentrations and mitigating their antimicrobial effects. Overexpression or mutations in efflux pump genes can enhance the expulsion of metal ions, potentially reducing their efficacy as antimicrobial agents. ...
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The rise in antimicrobial resistance (AMR) in Mycoplasma bovis underscores the urgent need for alternative treatments. This study evaluated the minimal inhibitory concentrations (MICs) of four metal ions (cobalt, copper, silver, and zinc) and colloidal silver against 15 clinical M. bovis isolates, alongside conventional antimicrobials (florfenicol, tetracycline, tulathromycin, and tylosin). Colloidal silver demonstrated the most effective antimicrobial activity, inhibiting 81.25% of isolates at 1.5 mg/L, while silver inhibited 93.7% of isolates at concentrations above 1.5 mg/L. Copper exhibited notable efficacy, inhibiting 37.5% of isolates at 1.5 mg/L, with a small proportion responding at 0.1 mg/L. Cobalt and zinc displayed variable activity, with MIC values ranging from 0.7 to 12.5 mg/L. In contrast, conventional antimicrobials showed limited effectiveness: tetracycline inhibited 31.25% of isolates at ≥16 mg/L, tylosin inhibited 25% at 16 mg/L, and tulathromycin MICs ranged from 0.5 to 8 mg/L. Time–kill assays revealed a reduction in M. bovis viability after eight hours of exposure to silver and colloidal silver, though higher concentrations (4×–8× MIC) were required for complete eradication. These findings highlight the significant potential of colloidal silver and copper as alternatives for treating M. bovis infections and combating AMR. Further research is essential to explore their standalone and synergistic applications for therapeutic use.
... In light of the results that we obtained, numerous antimicrobial resistance mechanisms associated with Vibrio isolates were identified. One of the most prevalent mechanisms among pathogenic bacteria is the efflux pump system, which plays a significant role in both intrinsic and acquired antibiotic resistance in bacteria [83,84]; moreover, it is instrumental in regulating the internal environment by expelling toxic substances, quorum-sensing molecules, biofilm formation molecules, and bacterial VFs [85]. Another identified resistance mechanism was antibiotic target modification, which has become an increasingly common resistance strategy among pathogenic bacteria [86]. ...
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Consuming raw or undercooked mussels can lead to gastroenteritis and septicemia due to Vibrio contamination. This study analyzed the prevalence, density, species diversity, and molecular traits of Vibrio spp. in 48 fresh raw wild mussels (FRMs) and 48 ready-to-eat stuffed mussels (RTE-SMs) through genome analysis, assessing health risks. The results showed Vibrio prevalence rates of 12.5% in FRMs and 4.2% in RTE-SMs, with V. alginolyticus as the most common species (46.7%). It was determined that the seasonal distribution of Vibrio spp. prevalence in the samples was higher in the summer months. The genome sizes of the Vibrio spp. ranged from approximately 3.9 to 6.1 Mb, with the GC contents varying between 41.9% and 50.4%. A total of 22 virulence factor (VF) classes and up to six antimicrobial resistance (AMR) genes were detected in different Vibrio species. The presence of nine different biosynthetic gene clusters (BGCs), 27 prophage regions, and eight CRISPR/Cas systems in 15 Vibrio strains provides information about their potential pathogenicity, survival strategies, and adaptation to different habitats. Overall, this study provides a comprehensive understanding of the genomic diversity of Vibrio spp. isolated from FRM and RTE-SM samples, shedding light on the prevalence, pathogenicity, and toxicity mechanisms of Vibrio-induced gastroenteritis.
... The efflux system enables bacteria to persist in harsh environments, including those with antimicrobial compounds. Efflux pumps exhibit resistance to several antibacterial agents belonging to the same or different families by using energy to reduce the concentration of drugs in the cytoplasm to sub-toxic levels [73]. The overproduction of efflux pumps contributes to a multidrug resistance (MDR) phenotype, often in combination with other resistance mechanisms such as target modification and antibiotic inactivation [74]. ...
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Biofilms, composed of structured communities of bacteria embedded in a self-produced extracellular matrix, pose a significant challenge due to their heightened resistance to antibiotics and immune responses. This review highlights the mechanisms underpinning antibiotic resistance within bacterial biofilms, elucidating the adaptive strategies employed by microorganisms to withstand conventional antimicrobial agents. This encompasses the role of the extracellular matrix, altered gene expression, and the formation of persister cells, contributing to the recalcitrance of biofilms to eradication. A comprehensive understanding of these resistance mechanisms provides a for exploring innovative therapeutic interventions. This study explores promising avenues for future research, emphasizing the necessity of uncovering the specific genetic and phenotypic adaptations occurring within biofilms. The identification of vulnerabilities in biofilm architecture and the elucidation of key biofilm-specific targets emerge as crucial focal points for the development of targeted therapeutic strategies. In addressing the limitations of traditional antibiotics, this review discusses innovative therapeutic approaches. Nanomate-rials with inherent antimicrobial properties, quorum-sensing inhibitors disrupting bacterial communication, and bacteriophages as biofilm-specific viral agents are highlighted as potential alternatives. The exploration of combination therapies, involving antimicrobial agents, biofilm-disrupting enzymes, and immunomodulators, is emphasized to enhance the efficacy of existing treatments and overcome biofilm resilience.
... Efflux pumps are another mechanism which allows the microorganisms to regulate their internal environment through toxic substances removal, including antimicrobial agents while quorum sensing is for communication and coordination for bacterial population also enhancing access to nutrients-rich niches, motility and plays a role in biofilm formation (Gaurav et al., 2023). Different pathogens broadly utilise three strategies to acquire the necessary nutrients for survival and replication from plant cells: (i) Manipulating host proteins to export nutrients to the apoplast where they reside (biotrophic), (ii) Causing the host cell to undergo programmed cell death and feeding on the remaining nutrients (necrotrophic), or (iii) A combination of the two approaches (hemi biotrophic) Persistence of opportunistic pathogens in soil and soil amendments: Many environmental and management factors that are employed introduce enteric pathogens to soil, these include raw manure, wastewater, human biosolids, compost, and wild and domestic animal intrusion and other anthropogenic activities (Gutierrez-Rodriguez and Adhikari, 2018). ...
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Leafy vegetables are a highly variable group of perishable food that broadly can be defined as vegetables grown for their edible leaves. This study was conducted to investigate the safety of commodities grown at farms and those sold in various retails globally, cascading to South Africa, and to determine the identification and characterization of the microbiota. Therefore, the authors conducted a desktop and literature review using popular trusted search engines with special keywords. For this study, the authors-maintained research material from 2010-2024, constituting research articles, reviews, book chapters, thesis, research short communications, and industrial short communications. From this study, it could be deduced that leafy green commodities differ from intact vegetables with regard to their physiology, handling, processing, and storage. In addition, various agronomic activities were identified as contributing to the contamination of leafy greens at various stages of minimal processing, including distribution. More studies have shown that various types of microorganisms are found in leafy vegetables purchased at small-scale farms and retail stores. Concerning that, characterise those that are pathogenic to human health and those that are beneficial and how to treat through antibiotics the diseases caused by those that are pathogenic to our health. Furthermore, the findings of this study revealed that some opportunistic pathogen communities in fresh leafy vegetables are diverse and can pose a health risk to consumers, leading to death. Finally, food safety and security remain a global challenge, and stunting continues to affect the majority of developing countries. Thus, future studies should focus on improving food safety management systems reducing food poisoning, recall incidents and outbreaks by controlling critical points and food security in primary horticulture production environments even at retail and determining which antimicrobials will inhibit the growth of specific bacteria causing a certain infection.