Recent advances toward a molecular mechanism of efflux pump inhibition

Area of Science:

• Microbiology
• Pharmacology
• Drug Discovery

Background:

• Gram-negative pathogens exhibit multidrug resistance (MDR), complicating infection treatment.
• Overexpression of Resistance-Nodulation-Division (RND)-type efflux pumps is a key mechanism driving MDR in bacteria.
• RND-type efflux pumps actively expel antibiotics and biocides from the bacterial periplasm.

Purpose of the Study:

• To review recent advancements in understanding the mechanisms of potent efflux pump inhibitors (EPIs) targeting RND-type pumps.
• To highlight the potential of EPIs as adjunctive therapies to combat MDR.
• To discuss challenges and opportunities in the rational design of novel EPIs.

Main Methods:

• Literature review of recent biochemical, computational, and structural studies on EPIs.
• Analysis of pre-clinically developed EPI series targeting RND-type efflux pumps.
• Examination of mechanisms of action for potent EPIs against Gram-negative bacteria.

Main Results:

• Several potent EPIs targeting RND-type efflux pumps have been identified and characterized.
• Three EPI series have undergone pre-clinical optimization, demonstrating potential therapeutic value.
• Lack of robust biochemical, computational, and structural methods has hindered clinical translation.

Conclusions:

• Efflux pump inhibitors represent a promising avenue for overcoming MDR in Gram-negative pathogens.
• Further development of rational drug design strategies is crucial for advancing EPIs to clinical application.
• EPIs could serve as vital adjunctive therapies, potentiating existing antibiotics and mitigating resistance emergence.