{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:51:52Z","timestamp":1780343512002,"version":"3.54.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014137","name":"Shanghai Shenkang Hospital Development Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014137","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007279","name":"Shanghai Municipal Health Bureau","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007279","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipalitya","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003395","name":"Shanghai Municipal Education Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003395","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"Background<\/jats:title>Multidrug-resistant (MDR) Pseudomonas aeruginosa<\/jats:italic> is a frequent opportunistic pathogen that causes significant mortality in patients with non-cystic fibrosis bronchiectasis (NCFB). Although the quorum sensing (QS) system is a potential target for treatment, lasR<\/jats:italic> mutants that present with a QS-deficient phenotype have been frequently reported among clinical P. aeruginosa<\/jats:italic> isolates. We aimed to investigate whether antibiotic resistance would select for lasR<\/jats:italic> mutants during chronic P. aeruginosa<\/jats:italic> lung infection and determine the mechanism underlying the phenomenon.<\/jats:p><\/jats:sec>Methods<\/jats:title>We prospectively evaluated episodes of chronic P. aeruginosa<\/jats:italic> lung infections in NCFB patients over a 2-year period at two centers of our institution. QS phenotypic assessments and whole-genome sequencing (WGS) of P. aeruginosa<\/jats:italic> isolates were performed. Evolution experiments were conducted to confirm the emergence of lasR<\/jats:italic> mutants in clinical MDR P. aeruginosa<\/jats:italic> cultures.<\/jats:p><\/jats:sec>Results<\/jats:title>We analyzed episodes of P. aeruginosa<\/jats:italic> infection among 97 NCFB patients and found only prior carbapenem exposure independently predictive of the isolation of MDR P. aeruginosa<\/jats:italic> strains. Compared with non-MDR isolates, MDR isolates presented significantly QS-deficient phenotypes, which could not be complemented by the exogenous addition of 3OC12-HSL. The paired isolates showed that their QS-phenotype deficiency occurred after MDR was developed. Whole-genome sequencing analysis revealed that lasR<\/jats:italic> nonsynonymous mutations were significantly more frequent in MDR isolates, and positive correlations of mutation frequencies were observed between genes of lasR<\/jats:italic> and negative-efflux-pump regulators (nalC<\/jats:italic> and mexZ<\/jats:italic>). The addition of the efflux pump inhibitor PA\u03b2N could not only promote QS phenotypes of these MDR isolates but also delay the early emergence of lasR<\/jats:italic> mutants in evolution experiments.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our data indicated that MDR P. aeruginosa<\/jats:italic> was predisposed to lasR<\/jats:italic> mutation through the upregulated activity of efflux pumps. These findings suggest that anti-QS therapy combined with efflux pump inhibitors might be a potential strategy for NCFB patients in the challenge of MDR P. aeruginosa<\/jats:italic> infections.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.934439","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T04:48:44Z","timestamp":1658897324000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Multidrug-resistant Pseudomonas aeruginosa is predisposed to lasR mutation through up-regulated activity of efflux pumps in non-cystic fibrosis bronchiectasis patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Fengming","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yishu","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris Tingshiuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.02752","article-title":"Role of the multidrug resistance efflux pump MexCD-OprJ in the pseudomonas aeruginosa quorum sensing response","volume":"9","author":"Alcalde-Rico","year":"2018","journal-title":"Front. 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