Efflux Pumping Mechanism of AcrB in Multidrug Resistance Bacteria

The AcrB is a multidrug pump in gram-negative bacteria responsible for ejecting antibiotics and other metabolic waste for its survival. Thus, understanding the expelling mechanisms of AcrB is essential in designing successful drugs. Though crystal structure of AcrB can be captured by the X-ray diffraction, the molecular details of AcrB-drug interaction are difficult to be identified by experiment. We have developed a hybrid coarse-grained molecular dynamics (MD) model to capture conformational changes of AcrB in presence of drug candidates at the distal binding pocket to understand the efflux mechanism. Binding energy of drugs with AcrB and potential of mean force (PMF) on drugs along the expelling pathway are also calculated. Our MD simulations show that AcrB monomer changes from binding state to extrusion state in the presence of drug or other substrate, if transmembrane residues Asp407 and/or 408 are being protonated by an antiport mechanism. Moreover, computed binding energy and PMF reveals that inhibitor-like drugs bind with AcrB much stronger than metabolic waste or conventional antibiotics. Our study suggests that inhibitor-like multifunctional drugs could effectively block AcrB pumping.