Recent Advances in Efflux Pump Inhibitors and Their Role in Combatting Multidrug Resistance

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: 31 December 2025 | Viewed by 1233

Special Issue Editors


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Guest Editor
Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary
Interests: clinical bacteriology; antibiotic resistance; multidrug efflux

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Guest Editor
Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm Square 10, H-6720 Szeged, Hungary
Interests: efflux systems of pathogenic bacteria; efflux pump inhibitors
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Special Issue Information

Dear Colleagues,

Antibiotic resistance poses an increasing challenge in modern medicine. Efflux pumps play a crucial role in bacterial resistance by expelling antibiotics out of the cells, thereby reducing their efficacy. Efflux pump inhibitors (EPIs) offer a promising solution to counteract this mechanism, enhancing the effectiveness of existing antibiotics. This Special Issue aims to gather the latest research on EPIs, focusing on molecular mechanisms, novel inhibitors, clinical applications, and resistance patterns.

Efflux pumps contribute significantly to bacterial multidrug resistance via various mechanisms, including biofilm formation and horizontal gene transfer. Recent studies have highlighted novel EPIs and their potential applications: 

  • New Efflux Systems: A novel major facilitator superfamily (MFS)-type tripartite efflux system, CprABC, was identified in Chryseobacterium PL22-22A, which mediates resistance to polymyxins. The flavonoid compound baicalin showed EPI activity against this system, highlighting new avenues for combatting resistance in Gram-negative bacteria​​;
  • Biofilm Inhibition: Efflux pumps have a dual role in biofilm formation, contributing to both the establishment and maintenance of biofilms. EPIs targeting these pumps have shown effectiveness in disrupting biofilm-related infections, providing new strategies for treating chronic infections associated with medical devices​​;
  • RND Efflux Pump Inhibitors: Synthetic inhibitors targeting RND efflux pumps, such as MexB and AcrB, have demonstrated significant potential in restoring antibiotic efficacy. These inhibitors work by targeting the expression, assembly, or activity of the efflux pump complexes​​;
  • Clinical Applications: EPIs have shown promise in reducing antibiotic resistance in clinical settings. Recent advancements include the development of compounds that enhance the susceptibility of multidrug-resistant bacteria to existing antibiotics, thereby extending the life span of current antimicrobial therapies​​.

Contributions of Previous Special Issue: The previous Special Issue, "The Role of Efflux Pump Inhibitors in Bacterial Multidrug Resistance", successfully published five articles out of seven submissions. These articles have, collectively, been viewed over 10,000 times and cited 19 times, indicating strong interest and impact in the research community. The first edition published 10 papers, further establishing the importance of this research area. 

Research on EPIs remains critical for addressing multidrug-resistant bacterial infections. The findings published in this Special Issue will contribute significantly to the development of new therapeutic strategies and the enhancement of antibiotic efficacy.

Dr. László Orosz
Dr. Spengler Gabriella
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • multidrug resistance
  • multidrug efflux pump
  • efflux pump inhibitor (EPI)
  • accumulation assay
  • efflux assay
  • fluorochromes
  • ethidium bromide
  • quorum sensing
  • biofilm

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Published Papers (1 paper)

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Review

16 pages, 2047 KB  
Review
Efflux-Mediated Resistance in Enterobacteriaceae: Recent Advances and Ongoing Challenges to Inhibit Bacterial Efflux Pumps
by Florent Rouvier, Jean-Michel Brunel, Jean-Marie Pagès and Julia Vergalli
Antibiotics 2025, 14(8), 778; https://doi.org/10.3390/antibiotics14080778 - 1 Aug 2025
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Abstract
Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire [...] Read more.
Efflux is one of the key mechanisms used by Gram-negative bacteria to reduce internal antibiotic concentrations. These active transport systems recognize and expel a wide range of toxic molecules, including antibiotics, thereby contributing to reduced antibiotic susceptibility and allowing the bacteria to acquire additional resistance mechanisms. To date, unlike other resistance mechanisms such as enzymatic modification or target mutations/masking, efflux is challenging to detect and counteract in clinical settings, and no standardized methods are currently available to diagnose or inhibit this mechanism effectively. This review first outlines the structural and functional features of major efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. It then explores various strategies used to curb their activity, with a particular focus on efflux pump inhibitors under development, detailing their structural classes, modes of action, and pharmacological potential. We discuss the main obstacles to their development, including the structural complexity and substrate promiscuity of efflux mechanisms, the limitations of current screening methods, pharmacokinetic and tissue distribution issues, and the risk of off-target toxicity. Overcoming these multifactorial barriers is essential to the rational development of less efflux-prone antibiotics or of efflux pump inhibitors. Full article
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