Yeast model predicts antifolate resistance mutations in unculturable lung pathogen Pneumocystis jirovecii

Researchers led by Francois D. Rouleau, Alexandre K. Dubé, and Christian R. Landry, publishing in PLOS Genetics, have developed a yeast-based system to study antifolate drug resistance in Pneumocystis jirovecii — the fungal pathogen responsible for Pneumocystis pneumonia (PCP) in immunocompromised individuals.

A fundamental obstacle in studying P. jirovecii is that the organism cannot be cultured in vitro or propagated in standard animal models. The team circumvented this by expressing the P. jirovecii dihydrofolate reductase (PjDHFR) enzyme — the target of trimethoprim and related antifolate drugs — in Saccharomyces cerevisiae. This surrogate system allowed systematic assessment of how specific mutations in PjDHFR alter susceptibility to trimethoprim and related compounds.

The approach provides a way to predict which naturally occurring DHFR variants are likely to confer clinically relevant resistance, an important question given that antifolate regimens remain the cornerstone of PCP treatment and prophylaxis. P. jirovecii cannot be subjected to conventional antimicrobial susceptibility testing, making genomic and computational approaches to resistance prediction particularly valuable.

The findings add to a growing toolkit for genomic-led understanding of resistance in obligate pathogens that resist culture, and may have downstream relevance for surveillance and treatment strategies in patients with HIV, haematological malignancies, and solid-organ transplants.