{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:22:52Z","timestamp":1790180572469,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Trimethoprim-sulfamethoxazole (SXT) is a possible alternative for the treatment of community- and hospital-acquired methicillin-resistant\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>\n                    (MRSA) due to the susceptibility of most MRSA strains to the drug. However, after long-term treatment with SXT, thymidine-dependent (TD) SXT-resistant small-colony variants (SCVs) emerge. In TD-SCVs, mutations of thymidylate synthase ([TS]\n                    <jats:italic>thyA<\/jats:italic>\n                    ) occur. Until now, it has never been systematically investigated that SXT is triggering the induction and\/or selection of TD-SCVs. In our study, we performed induction, reversion, and competition experiments\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a chronic mouse pneumonia model to determine the impact of SXT on the emergence of TD-SCVs. SCVs were characterized by light and transmission electron microscopy (TEM) and auxotrophism testing. Short-term exposure of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n                    to SXT induced the TD-SCV phenotype in\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n                    SH1000, while selection of TD-SCVs with\n                    <jats:italic>thyA<\/jats:italic>\n                    mutations occurred after long-term exposure. In reversion experiments with clinical and laboratory TD-SCVs, all revertants carried compensating mutations at the initially identified mutation site. Competition experiments\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    revealed a survival and growth advantage of the \u0394\n                    <jats:italic>thyA<\/jats:italic>\n                    mutant under low-thymidine availability and SXT exposure although this advantage was less profound\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Our results show that SXT induces the TD-SCV phenotype after short-term exposure, while long-term exposure selects for\n                    <jats:italic>thyA<\/jats:italic>\n                    mutations, which provide an advantage for TD-SCVs under specified conditions. Thus, our results further an understanding of the dynamic processes occurring during SXT exposure with induction and selection of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n                    TD-SCVs.\n                  <\/jats:p>","DOI":"10.1128\/aac.00742-15","type":"journal-article","created":{"date-parts":[[2015,9,14]],"date-time":"2015-09-14T21:51:14Z","timestamp":1442267474000},"page":"7265-7272","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":72,"title":["Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge"],"prefix":"10.1128","volume":"59","author":[{"given":"Andre","family":"Kriegeskorte","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola Ivan","family":"Lor\u00e8","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bragonzi","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Riva","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Kelkenberg","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Becker","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital of M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Proctor","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Wisconsin\u2014Madison, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Peters","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology, University Hospital of M\u00fcnster, M\u00fcnster, Germany"},{"name":"Interdisciplinary Centre for 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