{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:07:44Z","timestamp":1791724064225,"version":"4.3.4"},"reference-count":56,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T00:00:00Z","timestamp":1715126400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"the Guangdong Major Project of Basic and Applied Basic Research","award":["2020B0301030007"],"award-info":[{"award-number":["2020B0301030007"]}]},{"name":"MOST | National Key Research and Development Program of China","award":["2022YFC2303900"],"award-info":[{"award-number":["2022YFC2303900"]}]},{"name":"the Gurangdong Special Support Program Innovation Team","award":["2019BT02N054"],"award-info":[{"award-number":["2019BT02N054"]}]},{"name":"the Laboratory of Lingnan Modern Agriculture Project","award":["NT2021006"],"award-info":[{"award-number":["NT2021006"]}]},{"name":"the International Training Program for Outstanding Young Scientists in Universities in Guangdong Province","award":["HT202301811-02"],"award-info":[{"award-number":["HT202301811-02"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,5,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Antibiotic resistance could rapidly emerge from acquiring the mobile antibiotic resistance genes, which are commonly evolved from an intrinsic gene. The emergence of the plasmid-borne mobilized efflux pump gene cluster\n              <jats:italic>tmexCD1-toprJ1<\/jats:italic>\n              renders the last-resort antibiotic tigecycline ineffective, although its evolutionary mechanism remains unclear. In this study, we investigate the regulatory mechanisms of the progenitor NfxB-MexCD-OprJ, a chromosomally encoded operon that does not mediate antibiotic resistance in the wild-type version, and its homologs, TNfxB1-TMexCD1-TOprJ1 mediating high-level tigecycline resistance, and TNfxB3-TMexCD3-TOprJ1. Mechanistic studies demonstrated that in\n              <jats:italic>nfxB-mexCD-oprJ<\/jats:italic>\n              , MexCD expression was under a weaker promoter, P\n              <jats:italic>mexC<\/jats:italic>\n              and inhibited by a strong repressor NfxB. For\n              <jats:italic>tmexCD1-toprJ1<\/jats:italic>\n              , TMexCD1 was highly expressed owing to the presence of a strong promoter, P\n              <jats:italic>tmexC1<\/jats:italic>\n              , and an inactive suppressor, TNfxB1, with a T39R mutation that rendered it unable to bind to promoter DNA. In\n              <jats:italic>tnfxB3-tmexCD3-toprJ1b<\/jats:italic>\n              , TMexCD3 expression was intermediate because of the local regulator TNfxB3, which binds to two inverted repeat sequences of P\n              <jats:italic>tmexC<\/jats:italic>\n              . Additionally, TNfxB3 exhibited lower protein expression and weaker DNA binding affinity than its ancestor NfxB, together with their promoter activities difference explaining the different expression levels of\n              <jats:italic>tmexCD-toprJ<\/jats:italic>\n              homologs. Distinct fitness burdens on these homologs-carrying bacteria were observed due to the corresponding expression level, which might be associated with their global prevalence. In summary, our data depict the mechanisms underlying the evolution and dissemination of an important mobile antibiotic resistance gene from an intrinsic chromosomal gene.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                As antibiotic resistance seriously challenges global health, tigecycline is one of the few effective drugs in the pipeline against infections caused by multidrug-resistant pathogens. Our previous work identified a novel tigecycline resistance efflux pump gene cluster\n                <jats:italic>tmexCD1-toprJ1<\/jats:italic>\n                in animals and humans, together with its various variants, a rising clinical concern. Herein, this study focused on how the local regulation modes of\n                <jats:italic>tmexCD1-toprJ1<\/jats:italic>\n                evolved to a highly expressed efflux pump. Through comparative analysis between three\n                <jats:italic>tnfxB-tmexCD-toprJ<\/jats:italic>\n                homologs and their progenitor\n                <jats:italic>nfxB-mexCD-oprJ<\/jats:italic>\n                , modes, we demonstrated the evolutionary dynamics from a chromosomal silent gene to an active state. We found the de-repression of the local regulator and an increase of the promoter activity work together to promote a high production of drug efflux machines and enhance multidrug resistance. Our findings revealed that TMexCD1-TOprJ1 adopts a distinct evolutionary path to achieve higher multidrug resistance, urgently needing tight surveillance.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.00218-24","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T19:30:37Z","timestamp":1712086237000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Promoter regulatory mode evolution enhances the high multidrug resistance of\n            <i>tmexCD1-toprJ1<\/i>"],"prefix":"10.1128","volume":"15","author":[{"given":"Chengzhen","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Animal Disease Control and Prevention, Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China"},{"name":"Key Laboratory of Zoonosis of Ministry of Agricultural and Rural Affairs, National Risk Assessment Laboratory for Antimicrobial Resistant of Microorganisms in Animals, Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2543-1275","authenticated-orcid":false,"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Animal Disease Control and Prevention, Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China"},{"name":"Key Laboratory of Zoonosis of Ministry of Agricultural and Rural Affairs, National Risk Assessment Laboratory for Antimicrobial Resistant of Microorganisms in Animals, Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4662-8111","authenticated-orcid":false,"given":"Zeling","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-841X","authenticated-orcid":false,"given":"Luchao","family":"Lv","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Animal Disease Control and Prevention, Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China"},{"name":"Key Laboratory of Zoonosis of Ministry of Agricultural and Rural Affairs, National Risk Assessment Laboratory for Antimicrobial Resistant of Microorganisms in Animals, Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3526-7808","authenticated-orcid":false,"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Hong","sequence":"additional","affiliation":[{"name":"College of Life Sciences, South China Agricultural University, Guangzhou, China"},{"name":"Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, South China Agricultural University, Guangzhou, 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