Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria

Area of Science:

• Microbiology
• Pharmacology
• Medicinal Chemistry

Background:

• Antimicrobial resistance (AMR) is a critical global health issue, causing millions of deaths annually.
• The overexpression of multidrug efflux pumps in bacteria is a primary mechanism contributing to AMR.
• Gram-negative bacteria utilize these pumps to expel antibiotics, leading to treatment failures.

Purpose of the Study:

• To review and analyze various efflux pump inhibitors (EPIs) targeting Gram-negative bacteria.
• To explore the potential of EPIs in combating antimicrobial resistance.
• To provide a comparative analysis of different EPI families against *Escherichia coli* and *Pseudomonas aeruginosa*.

Main Methods:

• Literature review of existing efflux pump inhibitors.
• Analysis of structure-activity relationships and chemical synthesis pathways.
• Evaluation of *in vitro* and *in vivo* activities, pharmacological properties, binding sites, and mechanisms of action.

Main Results:

• Eight distinct families of EPIs active against *E. coli* and *P. aeruginosa* are presented.
• Detailed information on the chemical properties, biological activities, and mechanisms of action for each EPI family is provided.
• The review highlights the potential of these EPIs to restore antibiotic efficacy.

Conclusions:

• Efflux pump inhibitors represent a promising strategy to combat AMR.
• Further research and clinical development of EPIs are crucial to address the growing threat of antibiotic resistance.
• Targeting multidrug efflux pumps can revive existing antibiotic treatment options.