Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli

• Published in: ACS infectious diseases 2023-12, Vol.9 (12), p.2504-2522
• Main Authors: Pisoni, Lily A, Semple, Susan J, Liu, Sida, Sykes, Matthew J, Venter, Henrietta
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Bacterial Outer Membrane Proteins - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Escherichia coli; Escherichia coli Proteins - metabolism; Ligands; Membrane Transport Proteins - metabolism; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.3c00350

The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in . From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in . Seven compounds, including ivacaftor ( ), butenafine ( ), naftifine ( ), pimozide ( ), thioridazine ( ), trifluoperazine ( ), and meloxicam ( ), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor ( ) inhibited efflux dose dependently, had no effect on an strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.