Bacterial Multidrug Efflux Proteins: A Major Mechanism of Antimicrobial Resistance

Abstract

Antimicrobial resistance is a global challenge, for which the mechanisms of resistance are varied and complicated. Bacterial multidrug efflux proteins are a major mechanism of antimicrobial resistance and therefore, targets for drug development. Gram-negative bacteria are intrinsically more resistant to many antibiotics and biocides due to their cell structure and the activity of multidrug efflux proteins. These transporters actively extrude antibiotics and other xenobiotics from the cytoplasm or surrounding membranes of cells to the external environment. Based on amino acid sequence similarity, substrate specificity and the energy source used to export their substrates, there are seven major families of distinct bacterial multidrug efflux proteins: ABC, RND, MFS, SMR, MATE, PACE, AbgT. Individual proteins may be highly specialised for one compound or highly promiscuous, transporting a broad range of structurally dissimilar substrates. Protein structural organisation in a large majority of the families, including the number of transmembrane helices, has been confirmed by highresolution structure determination for at least one member. In this paper, we review the families of bacterial multidrug efflux proteins, including basic properties, energisation, structural organisation and molecular mechanism. Using representative proteins from each family, we also performed analyses of transmembrane helices, amino acid composition and distribution of charged residues. Ongoing characterisation of structure-function relationships and regulation of bacterial multidrug efflux proteins are necessary for contributing new knowledge to assist drug development and strategies that will overcome antimicrobial resistance.