{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T16:29:46Z","timestamp":1755793786787,"version":"3.44.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify genes related to eravacycline resistance in <jats:italic>Stenotrophomonas maltophilia<\/jats:italic> (<jats:italic>Sm<\/jats:italic>) and to provide a theoretical basis for the study of eravacycline resistance mechanisms in <jats:italic>Sm<\/jats:italic> and the development of new antibiotics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study employed an integrated omics approach: (1) <jats:italic>In vitro<\/jats:italic> antimicrobial susceptibility profiling via broth microdilution to determine baseline MICs for eravacycline and comparator drugs; (2) Induction of resistance in clinical <jats:italic>Sm<\/jats:italic> isolates (WJ_4, WJ_14, WJ_18) with low eravacycline MICs through serial passage in escalating drug concentrations; (3) Transcriptome sequencing (RNA-seq) and whole-genome sequencing (WGS) of <jats:italic>in vitro<\/jats:italic>-induced resistant strains (WJ_4a, WJ_14a, WJ_18a) and a clinical high-MIC isolate (WJ_97); (4) Bioinformatics analyses, including differential gene expression screening (with |log2(fold change)| &amp;gt; 2 and FDR-adjusted p &amp;lt; 0.05), SNP detection via GATK, and copy number variation (CNV) quantification using CCNE-acc to identify and compare resistance-related genetic alterations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Stable eravacycline-resistant strains were successfully induced, exhibiting 8- to 32-fold MIC increases. Transcriptome analysis revealed consistent upregulation of efflux pump genes (<jats:italic>smrA<\/jats:italic>, <jats:italic>smeD<\/jats:italic>, <jats:italic>smeE<\/jats:italic>, <jats:italic>smeF<\/jats:italic>) across all induced strains. CNV analysis demonstrated significant <jats:italic>smeDEF<\/jats:italic> locus amplification, while nonsynonymous mutations in <jats:italic>smeD<\/jats:italic>, <jats:italic>smeE<\/jats:italic>, and <jats:italic>smeF<\/jats:italic> occurred in WJ_14a (44 mutations) and WJ_18a (3 mutations) but not WJ_4a. The clinical strain WJ_97 showed distinct resistance architecture, including 65 upregulated nonsynonymous mutations (e.g., frameshift in <jats:italic>smeF<\/jats:italic>), mutations in <jats:italic>smeR<\/jats:italic>, <jats:italic>adeF<\/jats:italic>, and <jats:italic>vanY<\/jats:italic>-mediated target alteration, alongside a diverse resistance gene profile (41.4% inactivating enzymes, 34.4% efflux pumps). Global downregulation of cyclic AMP receptor protein (CRP) suggested synergistic multidrug resistance mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Eravacycline resistance in <jats:italic>Sm<\/jats:italic> is primarily driven by dysregulation of the <jats:italic>smeDEF<\/jats:italic> efflux complex, with <jats:italic>in vitro<\/jats:italic>-induced strains relying on CNV amplification and\/or coding mutations, while clinical isolates combine these with accessory pathways. This work provides the evidence for CNV as a core resistance driver and highlights evolutionary divergence under clinical pressure, informing future antibiotic development and resistance surveillance strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1632701","type":"journal-article","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T05:29:09Z","timestamp":1755235749000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Screening and comparison of in vitro-induced resistant and clinically resistant Stenotrophomonas maltophilia strains for eravacycline resistance-related genes"],"prefix":"10.3389","volume":"15","author":[{"given":"Jie","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiarong","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junchang","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1128\/AAC.04809-14","article-title":"Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City","volume":"59","author":"Abdallah","year":"2015","journal-title":"Antimicrobial Agents chemotherapy"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s40121-025-01170-x","article-title":"Clinical outcomes of eravacycline in patients treated for stenotrophomonas maltophilia infections","volume":"14","author":"Al Musawa","year":"2025","journal-title":"Infect. 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