Regulation of expression of the AcrAB-TolC efflux system of E. coli. Regulation of expression of the AcrAB-TolC efflux system of E. coli. Transcription of the acrAB and tolC genes is not genetically clustered but is often regulated by common regulators at multiple levels. The local repressor AcrR represses acrAB expression directly. Other regulators include the AcrS repressor of the AcrEF system, histone-like nucleoid structuring protein (H-NS), and the SdiA global regulator. Three global regulators, MarA, SoxS, and Rob, positively control the expression of acrAB, tolC, and micF. The micF transcript inhibits the translation of OmpF porin mRNA. The two-component regulatory systems EvgAS and/or PhoQP can enhance acrAB and tolC expression. The red lines show the repression of the transcription of the relevant gene by the repressors AcrR, AcrS, H-NS, MarR, and SoxR. The green arrowed lines reveal the activation of relevant gene expression by the activators MarA, SoxS, SdiA, Rob, EvgS, and PhoP (SoxS and Rob can also stimulate MarA expression). MarB modulates MarA expression. Several regulators can bind with certain ligands (such as antimicrobial agents and metabolites) or be induced by oxidative stress and thus become inactivated (in the case of AcrR, MarR, and SoxR) or activated (in the case of Rob when binding with bile salts or fatty acids). Mutational changes can lead to the inactivation of AcrR, AcrS, MarR, and SoxR. The crystal structures of AcrR, MarA, MarR, SoxR, and Rob are available with identified ligand-binding domains and conformational changes for regulation. Regulation of AcrAB by noncoding RNAs has also been identified (see the text). Overall, under various conditions, these multiple regulation mechanisms can together produce MDR by allowing simultaneously decreased influx (via OmpF porin) and increased efflux (via AcrAB-TolC) of antimicrobial agents, which can be captured by the pump complex from the outer and/or inner leaflets of the IM and the periplasm (but not directly from the cytosol). Expression of acrZ (whose product can be copurified with AcrB) is coregulated with that of acrAB via MarA, SoxS, and Rob. Xian-Zhi Li et al. Clin. Microbiol. Rev. 2015; doi:10.1128/CMR.00117-14