Mutations in the proximal binding site and F-loop of AdeJ confer resistance to efflux pump inhibitors

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dc.contributor.authorSaral Sariyer, Ayşegül
dc.contributor.authorLeus, Inga V.
dc.contributor.authorTambat, Rushikesh
dc.contributor.authorFarjana, Mithila
dc.contributor.authorOlvera, Marcela
dc.contributor.authorRukmani, Shalini J.
dc.contributor.authorSariyer, Emrah
dc.contributor.authorSmith, Jeremy C.
dc.contributor.authorParks, Jerry M.
dc.contributor.authorWalker, John K.
dc.contributor.authorZgurskaya, Helen I.
dc.date.accessioned2025-10-02T07:49:26Z
dc.date.available2025-10-02T07:49:26Z
dc.date.issued2025
dc.departmentAÇÜ, Sağlık Bilimleri Fakültesi, Beslenme ve Diyetetik Bölümü
dc.description.abstractMultidrug efflux is one of the major mechanisms of antibiotic resistance in gram-negative bacteria. Inhibitors of efflux pumps potentiate the activities of antibiotics, and their discovery could lead to new therapeutic options. The AdeIJK pump in Acinetobacter baumannii is a promising target for efflux pump inhibitors (EPIs) due to its high clinical importance and conservation, and several classes of EPIs targeting this and other A. baumannii efflux transporters have been recently reported. However, the mechanisms of action of these EPIs and their resistance liability remain underexplored. Here, we analyzed the impact of site-specific substitutions in the substrate/EPI translocation path of the inner membrane transporter AdeJ on efflux of substrate antibiotics and fluorescent probes and activities of substituted 4,6-diaminoquinoline EPIs. We found that substitutions in amino acid residues located in the entrance cleft (R701) and the flexible loop (E675) of AdeJ lead to resistance specifically against biphenyl-substituted EPIs, whereas the substitution of F178 in the distal binding pocket increased AdeJ sensitivity to certain naphthyl- and biphenyl-substituted EPIs. No major differences in docking scores and poses of substrates and EPIs were observed between the wild type and corresponding AdeJ variants for any of the mutations considered. This study concludes that substrates and EPIs bound along the translocation path of AdeJ participate in its conformational transitions and can either increase or decrease the rate of transport and therefore the efficiency of EPIs.
dc.identifier.doi10.1128/aac.00090-25
dc.identifier.issn00664804
dc.identifier.issue8
dc.identifier.pmid40626889
dc.identifier.scopus2-s2.0-105013156906
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://hdl.handle.net/11494/5951
dc.identifier.volume69
dc.identifier.wosWOS:001524013600001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakScopus
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.institutionauthorSaral Sariyer, Ayşegül
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.ispartofAntimicrobial Agents and Chemotherapy
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectAcinetobacter
dc.subjectAntibiotic resistance
dc.subjectEfflux pump inhibitors
dc.subjectMultidrug efflux
dc.titleMutations in the proximal binding site and F-loop of AdeJ confer resistance to efflux pump inhibitors
dc.typeArticle

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