{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:41:13Z","timestamp":1785400873208,"version":"3.56.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI132836"],"award-info":[{"award-number":["R01AI132836"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009224","name":"Advanced Research Projects Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009224","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,8,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Multidrug 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\n                      <jats:italic toggle=\"yes\">Acinetobacter baumannii<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">A. baumannii<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00090-25","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T09:57:47Z","timestamp":1751968667000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Mutations in the proximal binding site and F-loop of AdeJ confer resistance to efflux pump inhibitors"],"prefix":"10.1128","volume":"69","author":[{"given":"Aysegul","family":"Saral Sariyer","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]},{"id":[{"id":"https:\/\/ror.org\/02wcpmn42","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Nutrition and Dietetics, Faculty of Health Sciences, Artvin Coruh University","place":["Artvin, Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-717X","authenticated-orcid":true,"given":"Inga V.","family":"Leus","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rushikesh","family":"Tambat","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mithila","family":"Farjana","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Olvera","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini J.","family":"Rukmani","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01qz5mb56","id-type":"ROR","asserted-by":"publisher"}],"name":"Biosciences Division, Oak Ridge National Laboratory","place":["Oak Ridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emrah","family":"Sariyer","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]},{"id":[{"id":"https:\/\/ror.org\/02wcpmn42","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Nutrition and Dietetics, Faculty of Health Sciences, Artvin Coruh University","place":["Artvin, Turkey"]},{"id":[{"id":"https:\/\/ror.org\/02wcpmn42","id-type":"ROR","asserted-by":"publisher"}],"name":"Vocational School of Health Services, Medical Laboratory Techniques, Artvin Coruh University","place":["Artvin, Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy C.","family":"Smith","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01qz5mb56","id-type":"ROR","asserted-by":"publisher"}],"name":"Biosciences Division, Oak Ridge National Laboratory","place":["Oak Ridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3103-9333","authenticated-orcid":false,"given":"Jerry M.","family":"Parks","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01qz5mb56","id-type":"ROR","asserted-by":"publisher"}],"name":"Biosciences Division, Oak Ridge National Laboratory","place":["Oak Ridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Walker","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01p7jjy08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology and Physiology, School of Medicine, Saint Louis University","place":["St. Louis, USA"]},{"id":[{"id":"https:\/\/ror.org\/01p7jjy08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Saint Louis University","place":["St. Louis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8929-4727","authenticated-orcid":true,"given":"Helen I.","family":"Zgurskaya","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Oklahoma","place":["Norman, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_3_3_3_2","unstructured":"World Health O. 2024. 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