{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:27:09Z","timestamp":1786602429180,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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","award":["82260403"],"award-info":[{"award-number":["82260403"]}],"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","award":["32370195"],"award-info":[{"award-number":["32370195"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20252BAC200545"],"award-info":[{"award-number":["20252BAC200545"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20252BAC240499"],"award-info":[{"award-number":["20252BAC240499"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","award":["20252BAC220054"],"award-info":[{"award-number":["20252BAC220054"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    is a bacterium with high antimicrobial resistance to several drugs including carbapenems. Recently, resistance to cefiderocol (FDC), a new siderophore cephalosporin, has been reported despite its rare use in clinical practice. Therefore, this study aimed to investigate the dynamics of different resistance mechanisms in\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    that evolve under FDC pressure, as well as the interactions between these mechanisms in evolutionary trajectories to guide clinical medication.\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    ATCC 27853 was continuously induced with subinhibitory concentrations of cefiderocol\n                    <jats:italic>in vitro<\/jats:italic>\n                    to generate strains with different resistance levels. Phenotypic adaptability and molecular regulatory networks during the evolution of resistance were systematically elucidated using growth curves, pairwise competition assays, transcriptomics, RT-qPCR and efflux inhibition assays. The minimum inhibitory concentration (MIC) of the induced FDC-resistant strain increased from 0.125 to 64 \u03bcg\/mL. Simultaneously, the growth rate and peak declined below those of the parental strain. The pairwise competition assay showed that the relative fitness of resistant strains versus parental strains was &amp;lt; 1 in LB and ID-CAMHB broths. Transcriptome analysis revealed that the MIC of the induced FDC-resistant strain was related to the dose of efflux pumps, together with a layer-by-layer regulation of gene expression, to adapt to environmental stress. In the initial resistant strain, efflux pumps were slightly upregulated, and energy metabolism was downregulated. Conversely, in the strain with a MIC of 64 \u03bcg\/mL, efflux pumps were significantly up-regulated and drove bacterial reprogramming to induce resistance, particularly the RND efflux pump component oprM, along with multiple ABC transporters. RT-qPCR validated the significant upregulation of oprM, opuC, and opuBD (\n                    <jats:italic>p<\/jats:italic>\n                    &amp;lt; 0.05), confirming their central role. Furthermore, in the presence of the efflux pump inhibitor phenyl-arginine \u03b2-naphthylamide (PA\u03b2N), the resistant strains exhibited significantly reduced MICs for FDC. In conclusion, these data indicate that multiple mechanisms of action are involved in the antibacterial activity of\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    against FDC. Notably, the evolution of resistance was associated with the dose-dependent upregulation of core efflux pumps, complemented by stage-specific global physiological remodeling; however, it also came at a fitness cost.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1871230","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:32:31Z","timestamp":1786599151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From low- to high-level resistance: dynamic transcriptional adaptations and efflux pump amplification in cefiderocol-stressed Pseudomonas aeruginosa"],"prefix":"10.3389","volume":"17","author":[{"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Department II of Respiratory and Critical Care Medicine, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College","place":["Nanchang, China"]},{"name":"JXHC Key Laboratory of Respiratory Diseases, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanxu","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department II of Respiratory and Critical Care Medicine, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College","place":["Nanchang, China"]},{"name":"JXHC Key Laboratory of Respiratory Diseases, Jiangxi Provincial People\u2019s Hospital, The First Affiliated Hospital of Nanchang Medical College","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"School of Public Health, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"School of Public Health, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]},{"name":"Jiangxi Medical Center for Critical Public Health Events, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0005424","DOI":"10.1128\/jb.00054-24","article-title":"Non-interchangeable functions of efflux transporters of pseudomonas aeruginosa in survival under infection-associated stress.","volume":"206","author":"Adamiak","year":"2024","journal-title":"J. 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