Mutations of Drug Target Molecules in Pneumocystis jirovecii Isolates and Future Investigations

Abstract

Pneumocystis (Pc) jirovecii causes severe interstitial pneumonia in patients with immunodeficiency, in whom this fungus adheres with type-I alveolar epithelial cells. Therefore, it is important to perform quick diagnosis and treatment for Pc pneumonia (PcP). In general, a combination of two antifolate agents, sulfamethoxazole (inhibition of dihydropteroate synthase (DHPS)) and trimethoprim (inhibition of dihydrofolate reductase), is the first choice for PcP treatment, and pentamidine or atovaquone (inhibition of cytochrome b) are the alternative reagents for the therapy. Amino acid substitutions of drug-binding sites in DHPS shown in genotypic analysis have been reported to be associated with failures of prophylaxis / treatment or severe mortality for PcP, while there is another article showing a negative relationship between the DHPS mutations and poor prognosis. Drug sensitivity tests using the phenotypes as well as genotypes are necessary, although it is difficult to culture Pc. This review focuses on the relationship between mutations of drug-targeting molecules and treatment failure based on original data and other reports. In addition, trials of phenotypic analyses for Pc are described as promising investigations.