Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective

Abstract

The MacB ABC transporter forms a tripartite efflux pump with the MacA adaptor protein and TolC outer membrane exit duct to expel antibiotics and export virulence factors from Gram-negative bacteria. Here, we review recent structural and functional data on MacB and its homologs. MacB has a fold that is distinct from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores. In addition, many MacB-like ABC transporters do not form tripartite pumps, but instead operate in diverse cellular processes including antibiotic sensing, cell division and lipoprotein trafficking.

BceAB-Type Antibiotic Resistance Transporters Appear To Act by Target Protection of Cell Wall Synthesis

“…BceAB-type systems belong to the type VII ABC transporter superfamily, of which the Escherichia coli macrolide resistance transporter MacB is the paradigm example (22). MacB was recently shown to act according to a molecular bellows mechanism and expel its substrate from the periplasm across the outer membrane via the TolC exit duct by undergoing extensive conformational changes in its periplasmic domain (23).…”

An efflux inhibitor of the MacAB pump in Salmonella enterica serovar Typhimurium

“…Understanding the roles of the MacB in bacterial physiology is becoming an important issue. 24 In this study, we reported OU33858, an inhibitor of MacAB in Salmonella. This compound might be useful for the functional analysis of this efflux pump, including its role in bacterial physiology and drug resistance.…”

“…MacAB contributes to both drug‐resistant and virulent phenotypes in many Gram‐negative bacteria, including pathogenic species 24 . These pumps drive not only the efflux of macrolide antibiotics but also the transport of heat‐stable enterotoxin II, outer membrane glycolipids, lipopeptides, and protoporphyrin 25–28 .…”

“…Besides, the size range of MacB substrates (from about 0.5 kDa macrolides to 10 kDa proteins) requires explanation, including whether MacB recognizes substrates directly. Understanding the roles of the MacB in bacterial physiology is becoming an important issue 24 …”

“…MacAB contributes to both drug-resistant and virulent phenotypes in many Gram-negative bacteria, including pathogenic species. 24 These pumps drive not only the efflux of macrolide antibiotics but also the transport of heat-stable Experiments were repeated at least three times. The actual counted numbers of bacterial cells and each growth rates are shown in Table S1.…”