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Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge.
Antimicrob Agents Chemother. 2015 Dec; 59(12):7265-72.AA

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 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 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.

Authors+Show Affiliations

Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.Department of Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany Interdisciplinary Centre for Clinical Research, University of Münster, Münster, Germany.Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany kahl@uni-muenster.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26369968

Citation

Kriegeskorte, Andre, et al. "Thymidine-Dependent Staphylococcus Aureus Small-Colony Variants Are Induced By Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness During SXT Challenge." Antimicrobial Agents and Chemotherapy, vol. 59, no. 12, 2015, pp. 7265-72.
Kriegeskorte A, Lorè NI, Bragonzi A, et al. Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge. Antimicrob Agents Chemother. 2015;59(12):7265-72.
Kriegeskorte, A., Lorè, N. I., Bragonzi, A., Riva, C., Kelkenberg, M., Becker, K., Proctor, R. A., Peters, G., & Kahl, B. C. (2015). Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge. Antimicrobial Agents and Chemotherapy, 59(12), 7265-72. https://doi.org/10.1128/AAC.00742-15
Kriegeskorte A, et al. Thymidine-Dependent Staphylococcus Aureus Small-Colony Variants Are Induced By Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness During SXT Challenge. Antimicrob Agents Chemother. 2015;59(12):7265-72. PubMed PMID: 26369968.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge. AU - Kriegeskorte,Andre, AU - Lorè,Nicola Ivan, AU - Bragonzi,Alessandra, AU - Riva,Camilla, AU - Kelkenberg,Marco, AU - Becker,Karsten, AU - Proctor,Richard A, AU - Peters,Georg, AU - Kahl,Barbara C, Y1 - 2015/09/14/ PY - 2015/03/31/received PY - 2015/09/04/accepted PY - 2015/9/16/entrez PY - 2015/9/16/pubmed PY - 2016/9/1/medline SP - 7265 EP - 72 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 59 IS - 12 N2 - 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 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/26369968/Thymidine_Dependent_Staphylococcus_aureus_Small_Colony_Variants_Are_Induced_by_Trimethoprim_Sulfamethoxazole__SXT__and_Have_Increased_Fitness_during_SXT_Challenge_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=26369968 DB - PRIME DP - Unbound Medicine ER -