Expert opinion on drug discovery, 2012-07, Vol.7 (7), p.633-642
2012
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- Autor(en) / Beteiligte
- Titel
- Understanding efflux in Gram-negative bacteria: opportunities for drug discovery
- Ist Teil von
- Expert opinion on drug discovery, 2012-07, Vol.7 (7), p.633-642
- Ort / Verlag
- England: Informa UK, Ltd
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1746-0441eISSN: 1746-045XDOI: 10.1517/17460441.2012.688949Titel-ID: cdi_pubmed_primary_22607346
- Format
- –
- Schlagworte
- Anti-Bacterial Agents - metabolism, Anti-Bacterial Agents - pharmacology, Antibiotics, Antibodies, Antimicrobial agents, Attraction, Bacterial Proteins - drug effects, Bacterial Proteins - physiology, Biofilms, Biofilms - drug effects, Cell Membrane Permeability - drug effects, Cell Membrane Permeability - physiology, Cell Wall - drug effects, Cell Wall - physiology, Drug Discovery, Drug resistance, Drug Resistance, Multiple, Bacterial, efflux, Gene silencing, Gram-negative bacteria, Gram-Negative Bacteria - drug effects, Gram-Negative Bacteria - metabolism, Gram-Negative Bacteria - physiology, Humans, Infection, Lipopolysaccharides, Lipopolysaccharides - antagonists & inhibitors, Lipopolysaccharides - physiology, Membrane Transport Proteins - drug effects, Membrane Transport Proteins - physiology, Multidrug resistance, Outer membranes, Phages, Porins, Porins - drug effects, Porins - physiology, pump inhibition, Reviews, RNA Interference - drug effects, Stress, Virulence