AdeIJK pump-specific inhibitors effective against multidrug resistant acinetobacter baumannii

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dc.contributor.authorTambat, Rushikesh
dc.contributor.authorKinthada, Rama Kumar
dc.contributor.authorSaral Sarıyer, Ayşegül
dc.contributor.authorLeus, Inga V.
dc.contributor.authorSarıyer, Emrah
dc.contributor.authorD’Cunha, Napoleon
dc.contributor.authorZhou, Hinman
dc.contributor.authorLeask, Makaila
dc.contributor.authorWalker, John K.
dc.contributor.authorZgurskaya, Helen I.
dc.date.accessioned2024-12-11T06:30:48Z
dc.date.available2024-12-11T06:30:48Z
dc.date.issued2024
dc.departmentAÇÜ, Sağlık Bilimleri Fakültesi, Beslenme ve Diyetetik Bölümüen_US
dc.description.abstractMultidrug-resistant Acinetobacter baumannii is a serious threat pathogen rapidly spreading in clinics and causing a range of complicated human infections. The major contributor to A. baumannii antibiotic resistance is the overproduction of AdeIJK and AdeABC multidrug efflux pumps of the resistance-nodulation-division (RND) superfamily of proteins. The dominant role of efflux in antibiotic resistance and the relatively high permeability of the A. baumannii outer membrane to amphiphilic compounds make this pathogen a promising target for the discovery of clinically relevant efflux pump inhibitors. In this study, we identified 4,6-diaminoquoniline analogs with inhibitory activities against A. baumannii AdeIJK efflux pump and followed up on these compounds with a focused synthetic program to improve the target specificity and to reduce cytotoxicity. We identified several candidates that potentiate antibacterial activities of antibiotics erythromycin, tetracycline, and novobiocin not only in the laboratory antibiotic susceptible strain A. baumannii ATCC17978 but also in multidrug-resistant clinical isolates AB5075 and AYE. The best analogs potentiated the activities of antibiotics in low micromolar concentrations, did not have antibacterial activities on their own, inhibited AdeIJK-mediated efflux of its fluorescent substrate ethidium ion, and had low cytotoxicity in A549 human lung epithelial cells.
dc.identifier.doi10.1021/acsinfecdis.4c00190
dc.identifier.endpage2249en_US
dc.identifier.issn2373-8227
dc.identifier.issue6en_US
dc.identifier.scopusqualityQ1
dc.identifier.startpage2239en_US
dc.identifier.urihttp://dx.doi.org/10.1021/acsinfecdis.4c00190
dc.identifier.urihttps://hdl.handle.net/11494/5174
dc.identifier.volume10en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofACS Infectious Diseases
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/embargoedAccessen_US
dc.subjectAcinetobacter Baumanniien_US
dc.subjectEfflux Pump Inhibitorsen_US
dc.subjectMultidrug Efflux Pumpsen_US
dc.titleAdeIJK pump-specific inhibitors effective against multidrug resistant acinetobacter baumanniien_US
dc.typeArticle

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