{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:23:57Z","timestamp":1792931037024,"version":"4.5.0"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"51","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI140669"],"award-info":[{"award-number":["R01AI140669"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,17]]},"abstract":"<jats:p>\n                    The resistance-nodulation-cell division (RND) superfamily of multidrug efflux systems are important players in mediating antibiotic resistance in gram-negative pathogens.\n                    <jats:italic>Campylobacter jejuni<\/jats:italic>\n                    , a major enteric pathogen, utilizes an RND-type transporter system, CmeABC, as the primary mechanism for extrusion of various antibiotics. Recently, a functionally potent variant of CmeABC (named RE-CmeABC) emerged in clinical\n                    <jats:italic>Campylobacter<\/jats:italic>\n                    isolates, conferring enhanced resistance to multiple antibiotic classes. Despite the clinical importance of RE-CmeABC, the molecular mechanisms for its functional gain and its evolutionary trajectory remain unknown. Here, we demonstrated that amino acid substitutions in RE-CmeB (inner membrane transporter), but not in RE-CmeA (periplasmic protein) and RE-CmeC (outer membrane protein), in conjunction with a nucleotide mutation in the promoter region of the efflux operon, are responsible for the functional gain of the multidrug efflux system. We also showed that RE-\n                    <jats:italic>cmeABC<\/jats:italic>\n                    is emerging globally and distributed in genetically diverse\n                    <jats:italic>C. jejuni<\/jats:italic>\n                    strains, suggesting its possible spread by horizontal gene transfer. Notably, many of RE-\n                    <jats:italic>cmeABC<\/jats:italic>\n                    harboring isolates were associated with the human host including strains from large disease outbreaks, indicating the clinical relevance and significance of RE-CmeABC. Evolutionary analysis indicated that RE-\n                    <jats:italic>cmeB<\/jats:italic>\n                    likely originated from\n                    <jats:italic>Campylobacter coli<\/jats:italic>\n                    , but its expansion mainly occurred in\n                    <jats:italic>C. jejuni,<\/jats:italic>\n                    possibly driven by antibiotic selection pressure. Additionally, RE-\n                    <jats:italic>cmeB<\/jats:italic>\n                    , but not RE-\n                    <jats:italic>cmeA<\/jats:italic>\n                    and RE-\n                    <jats:italic>cmeC<\/jats:italic>\n                    , experienced a selective sweep and was progressing to be fixed during evolution. Together, these results identify a mutation-based mechanism for functional gain in RE-CmeABC and reveal the key role of RE-CmeB in facilitating\n                    <jats:italic>Campylobacter<\/jats:italic>\n                    adaptation to antibiotic selection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2415823121","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:15:10Z","timestamp":1732709710000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Mutation-based mechanism and evolution of the potent multidrug efflux pump RE-CmeABC in\n                    <i>Campylobacter<\/i>"],"prefix":"10.1073","volume":"121","author":[{"given":"Lei","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 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of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qijing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 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