Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

ABSTRACT

Introduction: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs.

Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed.

Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concentration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy.

KEYWORDS:

• Efflux pump
• Gram-negative bacteria
• antibiotic
• multidrug resistance
• inhibitor

Article highlights

• Efflux pumps play a major role in multidrug resistance in Gram-negative bacteria

• The pharmacodynamic role of RND efflux pumps in antibiotic resistance opens up new perspectives to alternative therapeutics

• Targeting efflux pumps consists in solving the problems of polyselectivity, drug accumulation, membrane permeability and pathogenicity related to bacterial resistance mechanisms

• How to validate efflux pumps as target for new combined therapy?

• Efflux pump inhibitor could be used as adjuvant in antibiotic treatments

This box summarizes key points contained in the article.

Acknowledgments

We appreciate greatly fruitful discussions and advices from Anne Davin-Regli and Jean-Michel Bolla.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by grant ANR-11-BS07-019-01 ‘IBEF’ Agence Nationale de la Recherche (ANR, France) and partly supported by Aix-Marseille University and IRBA.