Thymidine-dependent Staphylococcus aureus small-colony variants are induced by trimethoprim-sulfamethoxazole (SXT) and have increased fitness during SXT challenge

Andre Kriegeskorte, Nicola Ivan Lorè, Alessandra Bragonzi, Camilla Riva, Marco Kelkenberg, Karsten Becker, Richard A. Proctor, Georg Peters, Barbara C. Kahl

Research output: Contribution to journalArticle

Abstract

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 longterm 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 ΔthyA 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.

Original languageEnglish
Pages (from-to)7265-7272
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

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