{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:15:58Z","timestamp":1789402558405,"version":"build-2803163510"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/AuthorWarrantyLicense.v1"},{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | NIAID | Division of Intramural Research","award":["ZIA AI001079-16"],"award-info":[{"award-number":["ZIA AI001079-16"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,8,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              is a leading cause of healthcare-associated infections globally. Vancomycin-resistant\n              <jats:italic>S. aureus<\/jats:italic>\n              (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC) of 16\u201332 \u00b5g\/mL vancomycin], are uncommon, whereas vancomycin-intermediate\n              <jats:italic>S. aureus<\/jats:italic>\n              (VISA; MIC of 4\u20138 \u00b5g\/mL), are isolated more frequently and develop during long-term and\/or repeated use of the antibiotic. VISA can be difficult to eradicate and infections may persist. Our knowledge of mechanisms that underlie the development of VISA is incomplete. We used a genomics approach to investigate the VISA phenotype in three prominent\n              <jats:italic>S. aureus<\/jats:italic>\n              lineages. All VISA clinical isolates tested had increased cell wall thickness compared with vancomycin-susceptible\n              <jats:italic>S. aureus<\/jats:italic>\n              strains. Growth rates of clonal complex (CC) 5, CC8, and CC45 clinical isolates were reduced in 2 \u00b5g\/mL vancomycin compared to media alone. Culture in 2 and 4 \u00b5g\/mL vancomycin sequentially for two weeks reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin in a majority of CC5, CC8, and CC45 isolates tested. We identified alleles reported previously to contribute to the VISA phenotype, but unexpectedly, these alleles were unique to each CC. A subtherapeutic concentration of vancomycin elicited changes in the VISA transcriptome\u2014common and unique\u2014among the three CCs tested. Multiple genes, including those encoding a glycerate kinase, an M50 family metallopeptidase, and an uncharacterized membrane protein, were upregulated among all three lineages and not reported previously as associated with VISA. Although there are lineage-specific changes in DNA sequence, our findings suggest changes in the VISA transcriptome constitute a general response to stress that confers reduced susceptibility to multiple antibiotics.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Our understanding of the mechanisms that underlie the development of vancomycin-intermediate\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              (VISA) is incomplete. To provide a more comprehensive view of this process, we compared genome sequences of clonal complex (CC) 5, CC8, and CC45 VISA clinical isolates and measured changes in the transcriptomes of these isolates during culture with a subtherapeutic concentration of vancomycin. Notably, we identified differentially expressed genes that were lineage-specific or common to the lineages tested, including genes that have not been previously reported to contribute to a VISA phenotype. Changes in gene expression were accompanied by reduced growth rate, increased cell wall thickness, and reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin. Our results provide support to the idea that changes in gene expression contribute to the development of VISA among three CCs that are a prominent cause of human infections.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.00486-24","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T13:01:32Z","timestamp":1719320492000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Insights into the molecular basis of reduced vancomycin susceptibility among three prominent\n            <i>Staphylococcus aureus<\/i>\n            clonal complexes"],"prefix":"10.1128","volume":"12","author":[{"given":"Natalia","family":"Malachowa","sequence":"first","affiliation":[{"name":"Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Sturdevant","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline R.","family":"Porter","sequence":"additional","affiliation":[{"name":"Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Martin","sequence":"additional","affiliation":[{"name":"Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Martens","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Nair","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Hansen","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Ricklefs","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen G.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-2235","authenticated-orcid":true,"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0243-131X","authenticated-orcid":true,"given":"Barry N.","family":"Kreiswirth","sequence":"additional","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-2516","authenticated-orcid":true,"given":"Frank R.","family":"DeLeo","sequence":"additional","affiliation":[{"name":"Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","volume-title":"Global antimicrobial resistance and use surveillance system (\u200eGLASS)\u200e report: 2022","author":"WHO","year":"2022","unstructured":"WHO. 2022. 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