AcrB: a mean, keen, drug efflux machine

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Gram-negative bacteria possess intrinsic resistance to cytotoxic substances via their outer membrane and multidrug efflux systems.
• These systems, particularly the tripartite resistance-nodulation-cell division (RND) pumps like AcrAB-TolC in Escherichia coli, are vital for extruding drugs.
• The inner membrane component, AcrB, acts as the central hub for drug specificity and energy transduction in the efflux process.

Purpose of the Study:

• To review the molecular mechanisms of drug and inhibitor binding to the AcrB efflux pump.
• To elucidate the mechanistic insights into drug efflux mediated by AcrB.
• To summarize 17 years of mutational analysis of the acrB gene and its impact on antibiotic resistance in E. coli.

Main Methods:

• Literature review of molecular basis for drug binding and efflux.
• Analysis of published mutational data for the acrB gene.
• Recapitulation of mechanistic insights into AcrB function.

Main Results:

• AcrB functions via a cycle of three states in each protomer, forming an alternating access channel system for drug expulsion.
• The review compiles extensive data on mutations in acrB and their effects on antibiotic resistance.
• AcrB demonstrates functional robustness to single-site substitutions, though certain regions are more sensitive to perturbation.

Conclusions:

• AcrB is a key component of the AcrAB-TolC efflux system in E. coli, critical for multidrug resistance.
• Understanding AcrB's molecular mechanisms and mutational landscape provides insights into bacterial defense against antibiotics.
• The functional robustness and specific sensitivities of AcrB offer potential targets for novel antimicrobial strategies.