Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria

Leonard Amaral, Jean-Marie Pagès

Research output: Contribution to journalArticlepeer-review

217 Citations (Scopus)

Abstract

Chemoresistance presents a general health problem concerning the therapy of infectious disease and cancer. In this context, the worldwide dissemination of "multidrugresistant" (MDR) pathogens has severely reduced the efficacy of our antimicrobial weapons and dramatically increased the frequency of therapeutic failure. Because MDR bacterial infections involve the over-expression of efflux pumps that expel unrelated antibiotics before they can reach their targets, it is necessary to clearly define the molecular and genetic bases of the MDR mechanisms in order to combat these infectious diseases. This characterization of efflux pumps allows the definition of an original anti-resistance weapon, the efflux pump inhibitor (EPI). Several chemical families of EPIs have been now described and characterized. Among them several inhibitor compounds display an efficient activity and inhibit the major AcrAB-TolC and MexAB-OprM efflux systems which are the major efflux pumps responsible for MDR Gram negative clinical isolates. The use of these EPIs induces a significant reduction of resistance to one or more antibiotics to which these isolates were initially resistant. Hence, the EPI when used as an adjuvant to the given antibiotic, restores the activity of the antibiotic. The description of the responsible efflux mechanism at its structural and physiological level will make it possible to develop along intelligent lines an improved new generation of EPIs that can readily be added to the armamentarium of current and past "fallen by the wayside" antibiotic therapies. (C) 2009 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)826-833
Number of pages8
JournalBiochimica Et Biophysica Acta-Proteins And Proteomics
VolumeVol. 1794
Issue numbern.º 5
DOIs
Publication statusPublished - May 2009

Keywords

  • AcrAB-TolC
  • Antibiotic
  • Efflux pump
  • Chemosensitizer
  • Efflux pump inhibitor
  • Membrane channel
  • MexAB-OprM
  • Multidrug resistance
  • Gram negative bacteria
  • Transporter

Fingerprint

Dive into the research topics of 'Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria'. Together they form a unique fingerprint.

Cite this