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Although antibiotic-resistant\n                      <jats:italic toggle=\"yes\">Brucella<\/jats:italic>\n                      strains have been reported worldwide, the current status and underlying mechanisms of resistance among Chinese isolates remain poorly characterized. In this study, we analyzed 636 clinical human isolates of\n                      <jats:italic toggle=\"yes\">B. melitensis<\/jats:italic>\n                      from China using genomic sequencing, transcriptomic sequencing, and neural network prediction to identify key determinants and mechanisms of antibiotic resistance. Functional validations were performed using gene editing and protein-protein interaction assays. We found a gradual increase in resistance to trimethoprim-sulfamethoxazole (SXT) among Chinese isolates in recent years, despite the absence of known antibiotic resistance genes. Comparative genomic analyses between high- and low-minimum inhibitory concentration (MIC) isolates revealed specific single nucleotide polymorphisms (SNPs) that were present only in high-MIC isolates. Transcriptomic analysis demonstrated that high-MIC and low-MIC isolates activated distinct metabolic pathways in response to SXT exposure. Notably, genes influenced by specific SNPs exhibited opposing expression patterns after SXT treatment. Gene-editing experiments revealed that deletion of the glycoside hydrolase family 25 (GH25) gene, which was identified through SNP analysis, was associated with SXT resistance and notably altered\n                      <jats:italic toggle=\"yes\">Brucella<\/jats:italic>\n                      energy metabolism, although it did not impact virulence in host cells. Further, we identified a direct interaction between GH25 and XylF. Collectively, our study reveals a novel genetic mechanism driving SXT resistance in\n                      <jats:italic toggle=\"yes\">B. melitensis<\/jats:italic>\n                      . These findings highlight the critical need for vigilant surveillance of antibiotic resistance to mitigate public health risks associated with the potential widespread emergence of antibiotic resistance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01284-25","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:00:26Z","timestamp":1769090426000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Novel metabolic adaptation driven by glycoside hydrolase family 25 protein contributes to increasing trimethoprim-sulfamethoxazole resistance in clinical human\n                    <i>Brucella melitensis<\/i>\n                    isolates in China"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1909-9085","authenticated-orcid":true,"given":"Xiaowen","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0313jb750","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Animal Biosafety Risk Prevention and Control (North), Ministry of Agriculture and Rural Affairs, Institute of Animal Science, Chinese Academy of Agricultural Sciences","place":["Beijing, People's Republic of China"]},{"id":[{"id":"https:\/\/ror.org\/04f7g6845","id-type":"ROR","asserted-by":"publisher"}],"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention","place":["Beijing, People's Republic of 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