Review: Structure and regulation of the Acr efflux pumps and their role in antibiotic resistance in Escherichia coli
Multidrug resistance in Gram-negative bacterial pathogens is often mediated by efflux pumps that actively transport antibiotic compounds out of the cell. The AcrAB, AcrAD, and AcrEF proteins form such efflux pump complexes with the TolC protein, that confer resistance to a broad subset of antibiotics in Escherichia coli. In this review, we outline the genomic and protein structures and transcriptional regulation of AcrAB-TolC, AcrAD-TolC, and AcrEF-TolC. These tripartite systems are homologous, with differences in substrate specificity mainly attributed to the binding-site structure of their inner membrane transporters. On the genome, expression of the acrAB operon, acrD gene, and acrEF operon is modulated by multiple mechanisms, such as the local transcriptional repressors AcrS and AcrR, global transcriptional activators including regulators of the XylS/AraC family and H-NS, as well as transposable insertion elements IS186 and IS2. We conclude this review with a comparison of AcrS and AcrR regulation of the AcrAB, AcrAD, and AcrEF systems. We also discuss current knowledge gaps regarding the regulatory mechanisms that underlie Acr-mediated antibiotic resistance, particularly to kanamycin, that should be addressed in future studies.