Data Sheet 1_Targeting the AcrAB-TolC efflux pump by small molecules selectively addressing the outer membrane factor TolC.pdf

The major efflux pump in E. coli is the AcrAB-TolC complex that expels a broad spectrum of antibiotics from the bacterium, resulting in impaired efficacy of these drugs. Therefore, the inhibition of efflux pump function is an attractive approach to restore the susceptibility of Gram-negative bacteria for antibiotics.</p>Methods<p>A virtual screening campaign was utilized to identify potential TolC binders.

Virtual hits were investigated using a functional efflux assay, followed by synergy tests with piperacillin and determination of the intrinsic antibacterial potential. Bindings studies with individual efflux pump proteins were carried out. Synthetic chemistry was applied to improve the efficacy of the compound.