ArticleAntimicrobial agents and chemotherapy2013
Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).Annals of oncology : official journal of the European Society for Medical Oncology · 2015Guideline
- Predicting antifolate resistance in the unculturable fungal pathogen Pneumocystis jirovecii.PLoS genetics · 2026Article
- Predicting the Impact of Drug Resistance Mutations on Inhibitor Potency with Molecular Dynamics and Machine Learning.The journal of physical chemistry. B · 2025Article
- Metabolic modelling as a powerful tool to identify critical components of Pneumocystis growth medium.PLoS computational biology · 2024Article
- Deep mutational scanning of Pneumocystis jirovecii dihydrofolate reductase reveals allosteric mechanism of resistance to an antifolate.PLoS genetics · 2024Article
- The effect of antibiotic selection on collateral effects and evolvability of uropathogenicnpj antimicrobials and resistance · 2024Article
- Trimethoprim resistance in surface and wastewater is mediated by contrasting variants of the dfrB gene.The ISME journal · 2023Article
- Apparent Absence of Selective Pressure on Pneumocystis jirovecii Organisms in Patients with Prior Methotrexate Exposure.Antimicrobial agents and chemotherapy · 2022Article
- Highly ConservedAntimicrobial agents and chemotherapy · 2022Article
- Deciphering Antifungal Drug Resistance inJournal of chemical information and modeling · 2021Article
- Deciphering Complex Mechanisms of Resistance and Loss of Potency through Coupled Molecular Dynamics and Machine Learning.Journal of chemical theory and computation · 2021Article
- High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection.Molecular biology and evolution · 2019Article
- Site-Directed Mutagenesis of the 1,3-β-Glucan Synthase Catalytic Subunit ofAntimicrobial agents and chemotherapy · 2018Article
- Pathogenic Nocardia cyriacigeorgica and Nocardia nova Evolve To Resist Trimethoprim-Sulfamethoxazole by both Expected and Unexpected Pathways.Antimicrobial agents and chemotherapy · 2018Article
- A Molecular Window into the Biology and Epidemiology of Pneumocystis spp.Clinical microbiology reviews · 2018Review
- Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents.Bioorganic & medicinal chemistry · 2018Article
- In vitro and in vivo activity of iclaprim, a diaminopyrimidine compound and potential therapeutic alternative against Pneumocystis pneumonia.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2018Article
- Low prevalence of DHFR and DHPS mutations in Pneumocystis jirovecii strains obtained from a German cohort.Infection · 2017Article
- [Research progress on genes mutations related to sulfa drug resistance inZhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2017Review
- A Quantitative Model to Estimate Drug Resistance in Pathogens.Journal of fungi (Basel, Switzerland) · 2016Article
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
Pneumocystis jirovecii is an opportunistic pathogen that causes serious pneumonia in immunosuppressed patients. Standard therapy and prophylaxis include trimethoprim (TMP)-sulfamethoxazole; trimethoprim in this combination targets dihydrofolate reductase (DHFR). Fourteen clinically observed variants of P. jirovecii DHFR were produced recombinantly to allow exploration of the causes of clinically observed failure of therapy and prophylaxis that includes trimethoprim. Six DHFR variants (S31F, F36C, L65P, A67V, V79I, and I158V) showed resistance to inhibition by trimethoprim, with Ki values for trimethoprim 4-fold to 100-fold higher than those for the wild-type P. jirovecii DHFR. An experimental antifolate with more conformational flexibility than trimethoprim showed strong activity against one trimethoprim-resistant variant. The two variants that were most resistant to trimethoprim (F36C and L65P) also had increased Km values for dihydrofolic acid (DHFA). The catalytic rate constant (kcat) was unchanged for most variant forms of P. jirovecii DHFR but was significantly lowered in F36C protein; one naturally occurring variant with two amino acid substitutions (S106P and E127G) showed a doubling of kcat, as well as a Km for NADPH half that of the wild type. The strongest resistance to trimethoprim occurred with amino acid changes in the binding pocket for DHFA or trimethoprim, and the strongest effect on binding of NADPH was linked to a mutation involved in binding the phosphate group of the cofactor. This study marks the first confirmation that naturally occurring mutations in the gene for DHFR from P. jirovecii produce variant forms of DHFR that are resistant to trimethoprim and may contribute to clinically observed failures of standard therapy or prophylaxis.
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