Efflux Mechanisms

Trans-envelope multidrug efflux pumps of Gram-negative bacteria are the major contributors to antibiotic resistance in Gram-negative bacteria and potential targets for inhibition. These pumps are structurally and mechanistically diverse. P. aeruginosa chromosome contains multiple operons encoding multidrug efflux transporters. MexAB-OprM is the major “house-keeping” efflux pump, but it is not the only pump that is expressed and contributes to antibiotic resistance in this species. The constitutive expression of MexAB-OprM confers intrinsic antibiotic resistance, whereas elevated expression of MexXY-OprM is the major cause of aminoglycoside resistance in the absence of modifying enzymes. MexEF-OprN and MexGHI-OprD play important roles in P. aeruginosa physiology and are involved in the secretion of quorum-sensing signals and biofilm formation.

In the Center, both computational and experimental approaches are used to understand the mechanism of these pumps on cellular and molecular levels. The major efforts are to understand the dynamics of trans-envelope pump assemblies and to identify physico-chemical features of compounds that enable efflux inhibition and avoidance.

Lopez, C.A., T. Travers, K.M. Pos, Z. H.I., and S. Gnanakaran, Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface. Sci Rep, 2017. 7(1): p. 16251 DOI: 10.1038/s41598-017-16497-w
Ramaswamy, V.K., A.V. Vargiu, G. Malloci, J. Dreier, and P. Ruggerone, Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters. Sci Rep, 2017. 7(1): p. 8075 DOI: 10.1038/s41598-017-08747-8
Tikhonova, E.B., Y. Yamada, and H.I. Zgurskaya, Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chem Biol, 2011. 18(4): p. 454-63 DOI: 10.1016/j.chembiol.2011.02.011