{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:01Z","timestamp":1789020421238,"version":"build-2803163510"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQN25H190006"],"award-info":[{"award-number":["LQN25H190006"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202561"],"award-info":[{"award-number":["82202561"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017594","name":"Medical Science and Technology Project of Zhejiang Province","doi-asserted-by":"publisher","award":["2025KY560"],"award-info":[{"award-number":["2025KY560"]}],"id":[{"id":"10.13039\/501100017594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"\n Introduction<\/jats:title>\n \n Carbapenem-resistant\n Acinetobacter baumannii<\/jats:italic>\n (CRAB) poses a global health threat due to limited therapeutic options. Cefiderocol, a novel siderophore-conjugated cephalosporin, demonstrates potent\n in vitro<\/jats:italic>\n activity against a variety of Gram-negative bacteria, including CRAB. However, cefiderocol's recent introduction into clinical practice means that while several resistance mechanisms have been identified, their full characterization remains incomplete, and novel mechanisms are likely to emerge as clinical use expands.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this study,\n in vitro<\/jats:italic>\n evolution experiments were performed under cefiderocol pressure using a clinical CRAB isolate as the parental strain to investigate cefiderocol resistance mechanisms.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Genomic comparison and mutant reconstruction revealed that mutations in\n pbp1b<\/jats:italic>\n (G271R) and the intergenic region upstream of\n piuA<\/jats:italic>\n (-6_-8del) conferred a 4-fold increase in cefiderocol MIC.\n In silico<\/jats:italic>\n predictions and EMSA confirmed that the intergenic mutation occurred within the\n piuA<\/jats:italic>\n promoter region. qRT-PCR analysis indicated that the\n piuA<\/jats:italic>\n promoter mutation significantly reduced\n piuA<\/jats:italic>\n expression. This downregulation of\n piuA<\/jats:italic>\n expression impaired cefiderocol transport, leading to reduced susceptibility to cefiderocol. A search across publicly deposited genome sequences identified ten\n piuA<\/jats:italic>\n promoter mutations in\n A. baumannii<\/jats:italic>\n . Among these, the\u2212-6_-8del was the most commonly observed variant, which was primarily associated with ST2\n Pas<\/jats:sup>\n \/ST457\n Oxf<\/jats:sup>\n , ST2\n Pas<\/jats:sup>\n \/ST208\n Oxf<\/jats:sup>\n , and ST499\n Pas<\/jats:sup>\n . Functional characterization of the\u2212-6_-8del variant and three additional promoter mutations (-18del, A-17T&amp;-18del, A-17T&amp;-14del) confirmed suppression of\n piuA<\/jats:italic>\n expression and reduction of cefiderocol susceptibility.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n Combining\n in vitro<\/jats:italic>\n evolution with publicly available\n A. baumannii<\/jats:italic>\n genome sequences, this study demonstrates promoter-mediated\n piuA<\/jats:italic>\n downregulation as a cefiderocol resistance mechanism in\n A. baumannii<\/jats:italic>\n , providing a genomic target for predicting cefiderocol resistance.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1899246","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:31:19Z","timestamp":1789018279000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PiuA promoter mutations confer cefiderocol resistance in Acinetobacter baumannii: from in vitro evolution to global genomic screening"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaochen","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Zhejiang Hospital","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingye","family":"Xu","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Center, Zhejiang Center for Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"He","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Leptihn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, HMU Health and Medical University Erfurt","place":["Erfurt, Germany"]},{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark","place":["Odense, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunsong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang Provincial Engineering Research Center of Innovative Instruments for Precise Pathogen Detection","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Zhejiang Provincial Engineering Research Center of Innovative Instruments for Precise Pathogen Detection","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Zhejiang Hospital","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/1471-2180-13-158","article-title":"A method for generating marker-less gene deletions in multidrug-resistant Acinetobacter baumannii","volume":"13","author":"Amin","year":"2013","journal-title":"BMC Microbiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e0023423","DOI":"10.1128\/aac.00234-23","article-title":"Contribution of iron-transport systems and \u03b2-lactamases to cefiderocol resistance in clinical isolates of Acinetobacter baumannii endemic to New York City","volume":"67","author":"Asrat","year":"2023","journal-title":"Antimicrob. 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