Abstract
Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.
Novel nordihydroguaretic acid analogues were designed, synthesized and evaluated as AcrB inhibitors. [Display omitted]
•Novel nordihydroguaretic acid (NDGA) analogues were designed and synthesized.•They were evaluated as AcrB inhibitors against the E. coli BW25113.•Nine analogues were found to increase the efficacy of a panel of antibiotics.•Biochemical and docking studies were performed to determine AcrB inhibition.•They demonstrated moderate improvement in potency as compared to NDGA.