Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives

Significance AcrB is one of the major multidrug resistance-conferring antibiotic efflux pumps from pathogenic bacteria. We have designed and produced the periplasmic, substrate binding domain of AcrB and solved its crystal structure in complex with multiple novel pyranopyridine inhibitors, as well as with drugs transported by AcrB. The structural data are corroborated by various cellular assays and molecular dynamics (MD) simulations, and allow us to propose a mechanism for AcrB efflux inhibition. Furthermore, the results provide a molecular platform for the development of combinational therapies against pathogenic Enterobacteriaceae.