ArticleAntimicrobial agents and chemotherapy2015
Thymidine-Dependent Staphylococcus aureus Small-Colony Variants Are Induced by Trimethoprim-Sulfamethoxazole (SXT) and Have Increased Fitness during SXT Challenge.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- A systematic review of the clinical impact of small colony variants in patients with cystic fibrosis.BMC pulmonary medicine · 2023Pooled it
- GrowingInfection and immunity · 2026Article
- The β-lactam adjuvant guanosine potentiates anti-folate antibiotics and pyrimidine synthesis inhibitors by depleting thymidine in methicillin-resistantAntimicrobial agents and chemotherapy · 2026Article
- Targeting cGAS-STING signaling to overcome antibiotic-resistant bacterial infections: Challenges and opportunities.Science advances · 2026Review
- The β-lactam adjuvant guanosine potentiates anti-folate antibiotics and pyrimidine synthesis inhibitors by depleting thymidine in methicillin-resistantbioRxiv : the preprint server for biology · 2026Article
- Cyclic di-AMP inhibitsmBio · 2026Article
- State-of-the-Art Review: Transformative Changes in the Care of People With Cystic Fibrosis: Implications for Infectious Diseases Specialists.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2025Review
- Characterization ofInfection and drug resistance · 2025Article
- Mechanisms ofmBio · 2024Article
- Practical Guidance for Clinical Microbiology Laboratories: Updated guidance for processing respiratory tract samples from people with cystic fibrosis.Clinical microbiology reviews · 2024Review
- Integrative omics analysis reveals insights into small colony variants of Staphylococcus aureus induced by sulfamethoxazole-trimethoprim.BMC microbiology · 2024Article
- Validation of aminodeoxychorismate synthase and anthranilate synthase as novel targets for bispecific antibiotics inhibiting conserved protein-protein interactions.Applied and environmental microbiology · 2024Article
- Thymidine-dependent Staphylococcus aureus and lung function in patients with cystic fibrosis: a 10-year retrospective case-control study.Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia · 2024Article
- Article
- Acute Infection with a Tobramycin-Induced Small Colony Variant of Staphylococcus aureus Causes Increased Inflammation in the Cystic Fibrosis Rat Lung.Infection and immunity · 2022Article
- Thymidine starvation promotes c-di-AMP-dependent inflammation during pathogenic bacterial infection.Cell host & microbe · 2022Article
- Article
- Phenotypic Detection of Hemin-Inducible Trimethoprim-Sulfamethoxazole Heteroresistance in Staphylococcus aureus.Microbiology spectrum · 2021Article
- Emergence of Thymidine-Dependent Staphylococcus aureus Small-Colony Variants in Cystic Fibrosis Patients in Southern Brazil.Microbiology spectrum · 2021Article
- Antistaphylococcal Activity of the FtsZ Inhibitor C109.Pathogens (Basel, Switzerland) · 2021Article
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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