91桃色

Efflux pumps; Gram-negative bacteria; Antibiotic resistance; Multidrug resistance; RND family; ABC transporters; MFS transporters

Introduction

The rise of antibiotic resistance among Gram-negative bacteria has become a major global health crisis, leading to increased morbidity, mortality, and healthcare costs [1]. One of the key mechanisms contributing to antimicrobial resistance (AMR) in these pathogens is the activity of efflux pumps transport proteins that actively expel antibiotics and other toxic compounds from bacterial cells. By reducing intracellular drug concentrations, efflux pumps play a crucial role in decreasing the effectiveness of antimicrobial therapy and facilitating multidrug resistance (MDR) [2]. Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae have developed sophisticated efflux systems that enable them to survive in hostile environments, evade host immune responses, and resist multiple classes of antibiotics, including β-lactams, fluoroquinolones, aminoglycosides, and tetracyclines [3]. The Resistance-Nodulation-Division (RND), ATP-Binding Cassette (ABC), Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR), and Multidrug and Toxic Compound Extrusion (MATE) families represent the major efflux systems contributing to drug resistance in Gram-negative bacteria [4].

Beyond their role in antimicrobial resistance, efflux pumps are also implicated in bacterial virulence, biofilm formation, and adaptation to environmental stress. Given their broad impact on bacterial survival and pathogenicity, targeting efflux pump activity has emerged as a promising strategy to combat MDR Gram-negative infections. This paper explores the function, classification, and clinical significance of efflux pumps in antibiotic resistance, as well as potential therapeutic approaches to counteract their effects and improve treatment outcomes [5].

Discussion

Efflux pumps play a crucial role in the antibiotic resistance of Gram-negative bacteria by actively expelling antimicrobial agents, reducing their intracellular concentrations, and rendering treatment ineffective. These transport proteins are classified into several families, including the Resistance-Nodulation-Division (RND), ATP-Binding Cassette (ABC), Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR), and Multidrug and Toxic Compound Extrusion (MATE) systems, each contributing to resistance against multiple antibiotic classes [6]. Among them, the RND family, particularly AcrAB-TolC in Escherichia coli, MexAB-OprM in Pseudomonas aeruginosa, and AdeABC in Acinetobacter baumannii, is the most clinically relevant due to its broad substrate specificity and significant role in multidrug resistance (MDR). Efflux pumps are not only involved in antibiotic resistance but also enhance bacterial virulence, biofilm formation, and survival in hostile environments. Their overexpression, often triggered by genetic mutations or environmental stressors, leads to high-level resistance, making treatment options increasingly limited [7].

Given their impact on MDR, efflux pumps have become a major target for therapeutic intervention. Efflux pump inhibitors (EPIs), such as Phe-Arg-β-naphthylamide (PAβN) and verapamil, have shown potential in restoring antibiotic efficacy by blocking drug expulsion; however, their clinical application remains limited due to toxicity and specificity concerns [8]. Combination therapies using EPIs alongside existing antibiotics have demonstrated promise in overcoming resistance, particularly in pathogens like Acinetobacter baumannii. Alternative strategies, including phage therapy, antimicrobial peptides, and nanoparticle-based drug delivery, are also being explored to bypass efflux-mediated resistance. Another promising approach is targeting the regulatory mechanisms controlling efflux pump expression to prevent their overproduction. Despite these advancements, challenges such as bacterial adaptability, the lack of clinically approved EPIs, and limited understanding of efflux pump regulation continue to hinder the development of effective interventions [9].

Efforts to combat efflux-mediated resistance must involve a multidisciplinary approach integrating microbiology, genomics, structural biology, and pharmacology. Strengthening surveillance systems to monitor efflux-related resistance patterns, investing in novel antimicrobial therapies, and optimizing treatment strategies through personalized medicine are essential steps in mitigating the impact of MDR Gram-negative bacteria. As research advances, targeting efflux pumps remains a promising avenue to enhance the effectiveness of antibiotics and reduce the burden of drug-resistant infections worldwide [10].

Conclusion

Efflux pumps play a significant role in antibiotic resistance among Gram-negative bacteria by actively expelling antimicrobial agents, thereby reducing drug efficacy and contributing to multidrug resistance (MDR). Among the various efflux pump families, the Resistance-Nodulation-Division (RND), ATP-Binding Cassette (ABC), Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR), and Multidrug and Toxic Compound Extrusion (MATE) systems have been widely studied for their role in bacterial survival and resistance. These pumps not only reduce the effectiveness of multiple antibiotic classes but also contribute to bacterial virulence, biofilm formation, and persistence in healthcare setting Addressing efflux-mediated resistance requires a multifaceted approach, including the development of efflux pump inhibitors (EPIs), combination therapies, and alternative treatment strategies such as antimicrobial peptides and nanoparticle-based drug delivery systems. However, challenges such as bacterial adaptability, toxicity concerns of EPIs, and the lack of clinically approved inhibitors continue to hinder progress in this area. Strengthening antibiotic stewardship, enhancing surveillance programs, and advancing research into efflux pump regulation and inhibition will be crucial in mitigating the impact of MDR Gram-negative bacteria. Moving forward, a deeper understanding of efflux pump mechanisms, alongside innovative therapeutic interventions, will be essential to overcoming efflux-mediated resistance. By integrating scientific advancements with strategic antimicrobial policies, the global health community can make significant strides in preserving the efficacy of antibiotics and improving treatment outcomes for infections caused by drug-resistant Gram-negative bacteria.

References

1. Anderson S, Barton A, Clayton S (2021) Marine phytoplankton functional types exhibit diverse responses to thermal change. Nat Commun 12: 1-9.

Indexed at, Google Scholar, Crossref

2. Bopp L, Resplandy L, Orr J (2013) Multiple stressors of ocean ecosystems in the 21st century: projections with CMIP5 models. Biogeosciences 10: 6225-6245.

Indexed at, Google Scholar, Crossref

3. Boyd P, Collins S (2018) Experimental strategies to assess the biological ramifications of multiple drivers of global ocean change a review. Glob Chang Biol 24: 2239-2261.

Indexed at, Google Scholar, Crossref

4. Brennan G, Colegrave N, Collins S (2017) Evolutionary consequences of multidriver environmental change in an aquatic primary producer. Proceedings of the National Academy of Sciences of the United States of America 114: 9930-9935.

Indexed at, Google Scholar, Crossref

5. Burger F, Terhaar J, Frölicher T (2022) Compound marine heatwaves and ocean acidity extrems. Nat Commun 13: 1-12.

Indexed at, Google Scholar, Crossref

6. Chen B, Smith SL, Wirtz KW (2019) Effect of phytoplankton size diversity on primary productivity in the North Pacific: trait distributions under environmental variability. Ecol Lett 22: 56-66.

Indexed at, Google Scholar, Crossref

7. Cherabier P, Ferrière R (2022) Eco-evolutionary responses of the microbial loop to surface ocean warming and consequences for primary production. ISME J 16: 1130-1139.

Indexed at, Google Scholar, Crossref

8. Collins S, Rost B, Rynearson T (2014) Evolutionary potential of marine phytoplankton under ocean acidification. Evol Appl 7: 140-155.

Indexed at, Google Scholar, Crossref

9. Demory D, Baudoux A, Monier A (2019) Picoeukaryotes of the Micromonas genus: sentinels of a warming ocean. ISME J 13: 132-146.

Indexed at, Google Scholar, Crossref

10. DuRand M, Olson R, Chisholm S (2001) Phytoplankton population dynamics at the Bermuda Atlantic Time-series station in the Sargasso Sea. Deep-Sea Res. Part II: Top Stud Oceanogr 48: 1983-2003.

Indexed at, Google Scholar, Crossref