Discovery of multidrug efflux pump inhibitors with a novel chemical scaffold

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 6; p. 129546
• Main Authors: Green, Adam T., Moniruzzaman, Mohammad, Cooper, Connor J., Walker, John K., Smith, Jeremy C., Parks, Jerry M., Zgurskaya, Helen I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2020; Elsevier
• Subjects: Acinetobacter baumannii; antibiotic resistance; antimicrobial properties; Docking; erythromycin; Escherichia coli; Gram-negative; Gram-negative bacteria; Klebsiella pneumoniae; membrane fusion; Minimum inhibitory concentration; novobiocin; pathogens; Permeability; Resistance nodulation division; Substrate; transporters; Substrate; Docking; Permeability; Gram-negative; Minimum inhibitory concentration; Resistance nodulation division
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129546

Multidrug efflux is a major contributor to antibiotic resistance in Gram-negative bacterial pathogens. Inhibition of multidrug efflux pumps is a promising approach for reviving the efficacy of existing antibiotics. Previously, inhibitors targeting both the efflux transporter AcrB and the membrane fusion protein AcrA in the Escherichia coli AcrAB-TolC efflux pump were identified. Here we use existing physicochemical property guidelines to generate a filtered library of compounds for computational docking. We then experimentally test the top candidate coumpounds using in vitro binding assays and in vivo potentiation assays in bacterial strains with controllable permeability barriers. We thus identify a new class of inhibitors of E. coli AcrAB-TolC. Six molecules with a shared scaffold were found to potentiate the antimicrobial activity of erythromycin and novobiocin in hyperporinated E. coli cells. Importantly, these six molecules were also active in wild-type strains of both Acinetobacter baumannii and Klebsiella pneumoniae, potentiating the activity of erythromycin and novobiocin up to 8-fold. •Generated a focused library of compounds with specific physicochemical properties.•Performed ensemble docking of compounds to multiple sites on AcrA.•Measured in vivo activity of top compounds from docking.•Identified six molecules with a shared scaffold that potentiate antibiotic activity.