{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:04:07Z","timestamp":1789365847014,"version":"build-2803163510"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"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. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      is a major cause of bone, joint and orthopaedic implant-associated infections, providing clinical motivation for understanding adaptive antibiotic-response states. However, the present study is a secondary analysis of public\n                      <jats:italic>in vitro<\/jats:italic>\n                      transcriptomic and RNA-interaction datasets rather than an infection-model or clinical-specimen study. Vancomycin remains important for serious MRSA infections, but adaptive responses to vancomycin may vary across environmental and evolutionary states. Here, we used a framework integrating RefSeq-harmonized transcriptomics and RNA\u2013RNA interaction evidence to examine vancomycin response rewiring.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      In this secondary analysis, we performed a processed-expression reanalysis of public\n                      <jats:italic>S. aureus<\/jats:italic>\n                      transcriptomic and RNA-interaction datasets, using GSE149213 as the discovery dataset for medium-stratified vancomycin response modeling across cation-adjusted Mueller-Hinton broth (CA-MHB) and Roswell Park Memorial Institute medium supplemented with 10% lysogeny broth (RPMI + 10% LB) in wild-type, media-adapted control and analytically pooled vancomycin-evolved lineages\/populations. Candidate identities were harmonized using USA300HOU RefSeq locus-tag annotations, clean GSE254530 was used for conservative cross-dataset assessment, and published RNase III-CLASH data were used to evaluate candidate-associated RNA-interaction evidence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the exploratory GSE149213 processed-expression contrast analysis, analytically pooled vancomycin-evolved lineages\/populations retained broad acute responses, with the strongest response-rewiring burden corresponding to the EVO-WT response shift in RPMI + 10% LB; EVO-MAC response shifts were much more limited. RefSeq locus-tag harmonization retained a predefined nine-locus candidate panel for evidence ranking. Conservative GSE254530 assessment provided strict cross-dataset differential-expression support for pyrR only, while glnA was uniquely mapped but not differentially expressed and the remaining seven candidates lacked conservative clean-feature mappings. RNase III-CLASH integration highlighted carbamoyl-P synthase, dihydroorotase and glnA as top-ranked candidate-associated CLASH hotspots. Module-level processed-expression analysis further localized evolved response shifts to RPMI-associated redox\/stress, cell-wall\/envelope and proteolysis\/stress\/virulence programs, with translation\/ribosome showing a contrasting negative trend.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study provides a RefSeq-corrected, evidence-ranked processed-expression map of vancomycin response rewiring in\n                      <jats:italic>S. aureus<\/jats:italic>\n                      . Although the findings remain hypothesis-generating rather than causal, they define prioritized candidate loci, candidate-associated RNA-interaction edges and functional modules for future experimental testing in matched\n                      <jats:italic>in vitro<\/jats:italic>\n                      systems and biologically relevant infection models, including bone- and implant-associated models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1930249","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:38:58Z","timestamp":1789364338000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RefSeq-corrected transcriptomic and RNA-interaction integration maps medium-associated vancomycin response rewiring in Staphylococcus aureus"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhangfu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hospital Infection Management, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baicheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengji","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"783","DOI":"10.3390\/antibiotics12040783","article-title":"New antimicrobial resistance strategies: an adaptive resistance network conferring reduced glycopeptide susceptibility in VISA","volume":"12","author":"Aguglia","year":"2023","journal-title":"Antibiotics (Basel)"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1007\/s11274-024-04128-2","article-title":"Adaptive physiological and metabolic alterations in Staphylococcus aureus evolution under vancomycin exposure","volume":"40","author":"Cheng","year":"2024","journal-title":"World J. Microbiol. Biotechnol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1278228","DOI":"10.3389\/fbinf.2024.1278228","article-title":"Ten common issues with reference sequence databases and how to mitigate them","volume":"4","author":"Chorlton","year":"2024","journal-title":"Front Bioinform"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1111\/lam.13456","article-title":"Cell wall thickness and the molecular mechanism of heterogeneous vancomycin-intermediate Staphylococcus aureus","volume":"72","author":"Cui","year":"2021","journal-title":"Lett. Appl. Microbiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e0011525","DOI":"10.1128\/jb.00115-25","article-title":"Pyrimidine sufficiency is required for Sae two-component system signaling in Staphylococcus aureus","volume":"207","author":"DiMaggio","year":"2025","journal-title":"J. Bacteriol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"4892","DOI":"10.1093\/nar\/gku149","article-title":"A small RNA controls a protein regulator involved in antibiotic resistance in Staphylococcus aureus","volume":"42","author":"Eyraud","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/bs.ampbs.2024.04.006","article-title":"Staphylococcus aureus response and adaptation to vancomycin","volume":"85","author":"Fait","year":"2024","journal-title":"Adv. Microb. Physiol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"6734","DOI":"10.1038\/s41467-024-51144-9","article-title":"Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus","volume":"15","author":"Freiberg","year":"2024","journal-title":"Nat. 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Immunol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"D243","DOI":"10.1093\/nar\/gkae1038","article-title":"NCBI RefSeq: reference sequence standards through 25 years of curation and annotation","volume":"53","author":"Goldfarb","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1128\/jb.176.5.1460-1467.1994","article-title":"The femC locus of Staphylococcus aureus required for methicillin resistance includes the glutamine synthetase operon","volume":"176","author":"Gustafson","year":"1994","journal-title":"J. Bacteriol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"e0117624","DOI":"10.1128\/aac.01176-24","article-title":"A small regulatory RNA controls antibiotic adaptation in Staphylococcus aureus by modulating efflux pump expression","volume":"69","author":"Ha","year":"2025","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1241995","DOI":"10.3389\/fmicb.2023.1241995","article-title":"Teicoplanin associated gene tcaA inactivation increases persister cell formation in Staphylococcus aureus","volume":"14","author":"Habib","year":"2023","journal-title":"Front. Microbiol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"D762","DOI":"10.1093\/nar\/gkad988","article-title":"RefSeq and the prokaryotic genome annotation pipeline in the age of metagenomes","volume":"52","author":"Haft","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e1011531","DOI":"10.1371\/journal.ppat.1011531","article-title":"Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus","volume":"19","author":"Kim","year":"2023","journal-title":"PLoS Pathog."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e0089323","DOI":"10.1128\/aac.00893-23","article-title":"AgrA directly binds to the promoter of vraSR and downregulates its expression in Staphylococcus aureus","volume":"68","author":"Liu","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/s42003-021-02339-z","article-title":"Environmental conditions dictate differential evolution of vancomycin resistance in Staphylococcus aureus","volume":"4","author":"Machado","year":"2021","journal-title":"Commun. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e0048624","DOI":"10.1128\/spectrum.00486-24","article-title":"Insights into the molecular basis of reduced vancomycin susceptibility among three prominent Staphylococcus aureus clonal complexes","volume":"12","author":"Malachowa","year":"2024","journal-title":"Microbiol. Spectrum"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/s41579-022-00686-0","article-title":"Skeletal infections: microbial pathogenesis, immunity and clinical management","volume":"20","author":"Masters","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"3560","DOI":"10.1038\/s41467-022-31173-y","article-title":"RNase III CLASH in MRSA uncovers sRNA regulatory networks coupling metabolism to toxin expression","volume":"13","author":"McKellar","year":"2022","journal-title":"Nat. Commun."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"3558","DOI":"10.1038\/s41467-022-31177-8","article-title":"RNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3'UTR required for intermediate vancomycin resistance","volume":"13","author":"Mediati","year":"2022","journal-title":"Nat. Commun."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.tig.2020.08.016","article-title":"Networks of resistance: small RNA control of antibiotic resistance","volume":"37","author":"Mediati","year":"2021","journal-title":"Trends Genet."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1056\/NEJMra2203477","article-title":"Periprosthetic joint infection","volume":"388","author":"Patel","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41564-020-00819-2","article-title":"RNA antitoxin SprF1 binds ribosomes to attenuate translation and promote persister cell formation in Staphylococcus aureus","volume":"6","author":"Pinel-Marie","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1093\/ajhp\/zxaa036","article-title":"Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists","volume":"77","author":"Rybak","year":"2020","journal-title":"Am. J. Health Syst. Pharm."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1139\/cjm-2019-0048","article-title":"Oxidative stress resistance and fitness-compensatory response in vancomycin-intermediate Staphylococcus aureus (VISA)","volume":"65","author":"Tan","year":"2019","journal-title":"Can. J. Microbiol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e0097123","DOI":"10.1128\/msystems.00971-23","article-title":"The functional small RNA interactome reveals targets for the vancomycin-responsive sRNA RsaOI in vancomycin-tolerant Staphylococcus aureus","volume":"9","author":"Wu","year":"2024","journal-title":"mSystems"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1930249\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:38:58Z","timestamp":1789364338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1930249\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":31,"alternative-id":["10.3389\/fmicb.2026.1930249"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1930249","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"article-number":"1930249"}}