title: Understanding efflux in Gram-negative bacteria: opportunities for drug discovery.
abstract: BACKGROUND
  Bacteria evolved an arsenal of mechanisms to deal with toxic compounds and metabolic stresses, including antimicrobial agents. Efflux pumps are major players in the multidrug resistance of Gram-negative bacteria and pose major hurdles in the drug discovery process. However, recent advances in our understanding of efflux in these bacteria provide opportunities and assets for drug discovery.
  
  
  METHODS
  This review provides an overview of drug efflux in Gram-negative bacteria and its role in antimicrobial resistance, stress responses and other biological processes such as biofilm formation, and virulence. The discussion includes comments on the significance of synergy between a low-permeability outer membrane and efflux, notably the role of porins and lipopolysaccharide. The author then summarizes efforts aimed at inhibiting efflux pumps as a means to extend the utility of clinically useful antibiotics. This includes highlights of identification and characterization of small molecule efflux pump inhibitors (EPIs) from natural and synthetic sources, as well as novel strategies such as gene silencing and inhibitory antibodies.
  
  
  CONCLUSIONS
  Options for treating infections caused by multidrug-resistant bacteria are limited. Given the attractiveness of the therapeutic potential of efflux pump inhibition, further studies exploring novel strategies to interfere with efflux pump expression and function are warranted. This includes rational EPI design facilitated by pump structure information, exploitation of genetically defined efflux-proficient and efflux-compromised strain panels and non-traditional approaches such as pump inhibition by gene silencing, antibodies and perhaps even phage.
authors.affiliation: Colorado State University, IDRC at Foothills Campus, Department of Microbiology, Immunology and Pathology, Fort Collins, CO 80523-0922, USA. Herbert.Schweizer@colostate.edu
authors.forename: Herbert P
authors.initials: HP
authors.lastname: Schweizer
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000187:drug effects / Q000502:physiology; D018441:Biofilms / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D002473:Cell Wall / Q000187:drug effects / Q000502:physiology; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000502:physiology; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000502:physiology; D018272:Porins / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D018272:Porins