TY - JOUR
T1 - Understanding efflux in Gram-negative bacteria
T2 - Opportunities for drug discovery
AU - Schweizer, Herbert P.
N1 - Funding Information:
Work on bacterial efflux pumps in the author’s laboratory was supported by grants AI051588 and AI065357 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases.
PY - 2012/7
Y1 - 2012/7
N2 - Introduction: 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. Areas covered: 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. Expert opinion: 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.
AB - Introduction: 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. Areas covered: 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. Expert opinion: 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.
KW - Drug discovery
KW - Drug resistance
KW - Efflux
KW - Gram-negative bacteria
KW - Pump inhibition
UR - http://www.scopus.com/inward/record.url?scp=84862850350&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862850350&partnerID=8YFLogxK
U2 - 10.1517/17460441.2012.688949
DO - 10.1517/17460441.2012.688949
M3 - Review article
C2 - 22607346
AN - SCOPUS:84862850350
SN - 1746-0441
VL - 7
SP - 633
EP - 642
JO - Expert Opinion on Drug Discovery
JF - Expert Opinion on Drug Discovery
IS - 7
ER -