Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 59, Issue 12, Pages 7265-7272Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00742-15
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Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) [KA 2249/1-3, DFG Spp 1316, BE 2546/1-2]
- Interdisciplinary Center for Clinical Research (IZKF Munster) [Kah2/024/09]
- Transregional Collaborative Research Center 34
- Bundesministerium fur Bildung und Forschung (BMBF Medizinische Infektionsgenomik) [0315829B]
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Trimethoprim-sulfamethoxazole (SXT) is a possible alternative for the treatment of community-and hospital-acquired methicillin-resistant Staphylococcus aureus (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]thyA) 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 in vitro and in vivo 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 S. aureus to SXT induced the TD-SCV phenotype in S. aureus SH1000, while selection of TD-SCVs with thyA 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 in vitro and in vivo revealed a survival and growth advantage of the Delta thyA mutant under low-thymidine availability and SXT exposure although this advantage was less profound in vivo. Our results show that SXT induces the TD-SCV phenotype after short-term exposure, while long-term exposure selects for thyA 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 S. aureus TD-SCVs.
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