ArticleAntimicrobial agents and chemotherapy2005
Mutations in the Pneumocystis jirovecii DHPS gene confer cross-resistance to sulfa drugs.
Article in Antimicrobial agents and chemotherapy, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 39 citations in OpenAlex.
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- Highly ConservedAntimicrobial agents and chemotherapy · 2022Article
- Update on Dihydropteroate Synthase (DHPS) Mutations inJournal of fungi (Basel, Switzerland) · 2021Review
- Consensus Multilocus Sequence Typing Scheme forJournal of fungi (Basel, Switzerland) · 2020Review
- A Quantitative Model to Estimate Drug Resistance in Pathogens.Journal of fungi (Basel, Switzerland) · 2016Article
- A Case of Pneumonia Caused by Pneumocystis jirovecii Resistant to Trimethoprim-Sulfamethoxazole.The Korean journal of parasitology · 2015Article
- Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii.Antimicrobial agents and chemotherapy · 2013Article
- Pneumocystis jirovecii genotype associated with increased death rate of HIV-infected patients with pneumonia.Emerging infectious diseases · 2013Article
- Possible nosocomial transmission of Pneumocystis jirovecii.Emerging infectious diseases · 2012Article
- Delayed opportunistic infections in hematopoietic stem cell transplantation patients: a surmountable challenge.Hematology. American Society of Hematology. Education Program · 2012Review
- Article
- Serologic responses to pneumocystis proteins in HIV patients with and without Pneumocystis jirovecii pneumonia.Journal of acquired immune deficiency syndromes (1999) · 2011Article
- Crystal structures of Burkholderia cenocepacia dihydropteroate synthase in the apo-form and complexed with the product 7,8-dihydropteroate.BMC structural biology · 2011Article
- High prevalence of dihydropteroate synthase mutations in Pneumocystis jirovecii isolated from patients with Pneumocystis pneumonia in South Africa.Journal of clinical microbiology · 2010Article
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3 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP) and results in a high degree of mortality in immunocompromised individuals. The drug of choice for PCP is typically sulfamethoxazole (SMX) or dapsone in conjunction with trimethoprim. Drug treatment failure and sulfa drug resistance have been implicated epidemiologically with point mutations in dihydropteroate synthase (DHPS) of P. jirovecii. P. jirovecii cannot be cultured in vitro; however, heterologous complementation of the P. jirovecii trifunctional folic acid synthesis (PjFAS) genes with an E. coli DHPS-disrupted strain was recently achieved. This enabled the evaluation of SMX resistance conferred by DHPS mutations. In this study, we sought to determine whether DHPS mutations conferred sulfa drug cross-resistance to 15 commonly available sulfa drugs. It was established that the presence of amino acid substitutions (T(517)A or P(519)S) in the DHPS domain of PjFAS led to cross-resistance against most sulfa drugs evaluated. The presence of both mutations led to increased sulfa drug resistance, suggesting cooperativity and the incremental evolution of sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine [SCP] and sulfamethoxypyridazine [SMP]) that had a higher inhibitory potential than SMX were identified. In addition, SCP, SMP, and sulfadiazine (SDZ) were found to be capable of inhibiting the clinically observed drug-resistant mutants. We propose that SCP, SMP, and SDZ should be considered for clinical evaluation against PCP or for future development of novel sulfa drug compounds.
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