Multidrug resistance (MDR) provokes obstruction in disease control by intensifying the possibility of spreading of resistant pathogens. It declines efficacy of treatment and, hence, resulting in prolonged time of infection in patient. A major contributor to bacterial MDR is the overexpression of multidrug efflux pumps. Additionally, they export a broad variety of structurally and/or chemically unrelated antimicrobials out of cells. Besides, one of the most-studied efflux systems in Gram-negative bacteria is the tripartite AcrAB-TolC pump from Escherichia coli. It comprises an internal membrane transporter, an outer membrane exit duct, and a periplasmic adaptor. The resistance-nodulation-cell division transporter AcrB is responsible for energy transduction and substrate recognition in the tripartite AcrAB-TolC efflux system in Escherichia coli.

Despite a broad substrate specificity, only a few compounds have been cocrystallized with AcrB inside the distal binding pocket (DBP). D13-9001 is a promising efflux pump inhibitor that potentiates the efficacy of a wide variety of antibiotics. Zuo et al has compared the binding and extrusion processes of this inhibitor and the substrate doxorubicin in AcrB. With respect to doxorubicin, the interaction of D13-9001 with the hydrophobic trap results in delayed disassociation from the DBP. Notably, the detachment of D13-9001 is tightly correlated with the side-chain reorientation of Phe628 and large-scale displacement of Tyr327. Furthermore, the inhibitor induces much more significant conformational changes at the exit gate than DOX does.  So it causes higher energy cost for extrusion and contributing to the inhibitory effect in addition to the tight binding at DBP. Ranjitkar et al also reported that D13-9001 specifically inhibits MexAB-OprM in Pseudomonas aeruginosa Mutants with decreased susceptibility.

Reference:
J Phys Chem B. 2016 Mar 10;120(9):2145-54.