AcrB: a mean, keen, drug efflux machine

Abstract

Gram-negative bacteria are intrinsically resistant against cytotoxic substances by means of their outer membrane and a network of multidrug efflux systems, acting in synergy. Efflux pumps from various superfamilies with broad substrate preferences sequester and pump drugs across the inner membrane to supply the highly polyspecific and powerful tripartite resistance-nodulation-cell division (RND) efflux pumps with compounds to be extruded across the outer membrane barrier. In Escherichia coli, the tripartite efflux system AcrAB-TolC is the archetype RND multiple drug efflux pump complex. The homotrimeric inner membrane component acriflavine resistance B (AcrB) is the drug specificity and energy transduction center for the drug/proton antiport process. Drugs are bound and expelled via a cycle of mainly three consecutive states in every protomer, constituting a flexible alternating access channel system. This review recapitulates the molecular basis of drug and inhibitor binding, including mechanistic insights into drug efflux by AcrB. It also summarizes 17 years of mutational analysis of the gene acrB, reporting the effect of every substitution on the ability of E. coli to confer resistance toward antibiotics (http://goethe.link/ AcrBsubstitutions). We emphasize the functional robustness of AcrB toward single-site substitutions and highlight regions that are more sensitive to perturbation.

Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter from Salmonella

“…Salmonella is an important Gram-negative pathogen, the prevalence of which is increasing especially in nosocomial settings. While there are many adaptive routes for the development of MDR in Salmonella [ 1 ], the role of the multidrug efflux-pumps in the process has been identified as one of the key mechanisms for escaping the antibiotic and biocide selective pressures [ 2 , 3 , 4 ]. The action of the resistance-nodulation-division (RND) transporter AcrB provides the principal antimicrobial resistance efflux function in Salmonella enterica serovar Typhimurium (from here on, S. Typhimurium) [ 5 ].…”

Determination of Drug Efflux Pump Efficiency in Drug-Resistant Bacteria Using MALDI-TOF MS

“…AcrB, the most studied transporter in the RND family, is a trimeric inner membrane transporter that confers resistance to a wide range of antibiotics (e.g., tetracycline, chloramphenicol, β-lactams, novobiocin, fusidic acid, nalidixic acid and fluoroquinolones), detergents (e.g., sodium dodecyl sulfate [SDS] and Triton X-100), various cationic dyes, disinfectants and even solvents [ 27 ]. The pSYC-acrB expression construct was transformed into the E .…”

Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

“…As such, they represent a viable alternative to gain insights into the binding of compounds to AcrB. One of the earlier studies on this protein identified two distinct sub portions of the DP T , called "groove" and "cave" [44,45]. The groove region is located in the upper portion of the DP T , close to the so-called exit gate (EG , Table S1) [15], while the broader cave region is located at the bottom of the DP T .…”