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Combined structure- and ligand-based approach for the identification of inhibitors of AcrAB-TolC in Escherichia coli

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dc.contributor.authorPisoni, L.A.
dc.contributor.authorSemple, S.J.
dc.contributor.authorLiu, S.
dc.contributor.authorSykes, M.J.
dc.contributor.authorVenter, H.
dc.date.issued2023
dc.descriptionData source: Supporting Information, https://doi.org/10.1021/acsinfecdis.3c00350
dc.description.abstractThe 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 Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli 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.
dc.identifier.citationACS Infectious Diseases, 2023; 9(12):2504-2522
dc.identifier.doi10.1021/acsinfecdis.3c00350
dc.identifier.issn2373-8227
dc.identifier.issn2373-8227
dc.identifier.urihttps://hdl.handle.net/11541.2/36776
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.fundingNHMRC 1147538
dc.relation.fundingAustralian Government Research Training Program (RTP) Scholarship
dc.rightsCopyright 2023 American Chemical Society Access Condition Notes: Accepted manuscript available after 1 January 2025
dc.source.urihttps://doi.org/10.1021/acsinfecdis.3c00350
dc.subjectefflux pump inhibitor
dc.subjectmultidrug efflux
dc.subjectdrug repurposing
dc.subjectantimicrobial resistance
dc.subjectresistance breaker
dc.subjectAcrB
dc.titleCombined structure- and ligand-based approach for the identification of inhibitors of AcrAB-TolC in Escherichia coli
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12277668570001831 13277658780001831 Open Access Postprint
ror.mmsid9916803429201831

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