Abstract
Drug efflux protein complexes confer multidrug resistance on bacteria by transporting a wide spectrum of structurally diverse antibiotics. Moreover, organisms can only acquire resistance in the presence of an active efflux pump. The substrate range of drug efflux pumps is not limited to antibiotics, but it also includes toxins, dyes, detergents, lipids, and molecules involved in quorum sensing; hence efflux pumps are also associated with virulence and biofilm formation. Inhibitors of efflux pumps are therefore attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. Recent successes on the structure determination and functional analysis of the AcrB and MexB components of the AcrAB-TolC and MexAB-OprM drug efflux systems as well as the structure of the fully assembled, functional triparted AcrAB-TolC complex significantly contributed to our understanding of the mechanism of substrate transport and the options for inhibition of efflux. These data, combined with the well-developed methodologies for measuring efflux pump inhibition, could allow the rational design, and subsequent experimental verification of potential efflux pump inhibitors (EPIs). In this review we will explore how the available biochemical and structural information can be translated into the discovery and development of new compounds that could reverse drug resistance in Gram-negative pathogens. The current literature on EPIs will also be analyzed and the reasons why no compounds have yet progressed into clinical use will be explored.
Highlights
Over the last two decades there has been a dramatic surge in the number of multidrug resistant bacteria, yet paradoxically the number of pharmaceutical companies developing new antimicrobial agents has dwindled during this same period
Infections caused by Gram-negative pathogens proved much harder to treat due to the very high intrinsic drug resistance displayed by Gram-negative organisms
There are various papers reporting the ability of crude extracts from plants or other organisms to reduce antibiotic resistance that were not dealt with in this review
Summary
Over the last two decades there has been a dramatic surge in the number of multidrug resistant bacteria, yet paradoxically the number of pharmaceutical companies developing new antimicrobial agents has dwindled during this same period. Drug efflux pumps are protein complexes which reside in the membrane and remove antimicrobials and toxins, thereby lowering their concentration inside the cell to sub-toxic levels (Poole, 2004, 2005; Piddock, 2006a; Nikaido and Pages, 2012) These proteins recognize and expel a wide range of structurally diverse antibiotics with different mechanisms and sites of action. Very recently Du et al (2014) used a creative approach of genetic fusion proteins to solve the first structure of a partially active, fully assembled, tripartite pump in the presence of a modulatory partner This structure of AcrA–AcrB–AcrZ–TolC shed light on long disputed subunit stoichiometries and revealed that the complex assembles in a 3 : 6 : 3 ratio of AcrB : AcrA : TolC with one monomer of AcrZ bound to each subunit of AcrB. Our current understanding of the structure and function of RND efflux pumps from Gram-negative bacteria could provide the basis for the informed and efficient design of inhibitors against these protein complexes
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