Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view.
The efflux systems of bacteria protect cells from antibiotics and biocides by actively transporting compounds out of the cytoplasm and/or periplasm and thereby limit their steady-state accumulation at their site(s) of action. The impact of efflux systems on the efficacy of antibiotics used in human medicine and animal husbandry is becoming increasingly apparent from the characterization of drug-resistant strains with altered drug efflux properties. In most instances, efflux-mediated antibiotic resistance arises from mutational events that result in their elevated expression and, in the case of efflux pumps with broad substrate specificity, can confer multi-drug resistance (MDR) to structurally unrelated antibiotics. Knowledge of the role of efflux systems in conferring antibiotic resistance has now been successfully exploited in the pharmaceutical industry and contributed, in part, to the development of new members of the macrolide and tetracycline classes of antibiotics that circumvent the efflux-based resistance mechanisms that have limited the clinical utility of their progenitors. The therapeutic utility of compounds that inhibit bacterial drug efflux pumps and therein potentiate the activity of a co-administered antibiotic agent remains to be validated in the clinical setting, but the approach holds promise for the future in improving the efficacy and/or extending the clinical utility of existing antibiotics. This review discusses the potential of further exploiting the knowledge of efflux-mediated antibiotic resistance in bacteria toward the discovery and development of new chemotherapeutic agents.
Lynch
A Simon
AS
Cumbre Inc., 1502 Viceroy Drive, Dallas, TX 75235-2304, USA. simon.lynch@cumbre.biz
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D004345:Drug Industry; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D026901:Membrane Transport Proteins