Functional Characterization of the Pneumocystis jirovecii Potential Drug Targetsdhfsandabz2Involved in Folate Biosynthesis

Abstract

ABSTRACTPneumocystisspecies are fungal parasites colonizing mammal lungs with strict host specificity.Pneumocystis jiroveciiis the human-specific species and can turn into an opportunistic pathogen causing severe pneumonia in immunocompromised individuals. This disease is currently the second most frequent life-threatening invasive fungal infection worldwide. The most efficient drug, cotrimoxazole, presents serious side effects, and resistance to this drug is emerging. The search for new targets for the development of new drugs is thus of utmost importance. The recent release of theP. jiroveciigenome sequence opens a new era for this task. It can now be carried out on the actual targets to be inhibited instead of on those of the relatively distant modelPneumocystis carinii, the species infecting rats. We focused on the folic acid biosynthesis pathway because (i) it is widely used for efficient therapeutic intervention, and (ii) it involves several enzymes that are essential for the pathogen and have no human counterparts. In this study, we report the identification of two such potential targets within the genome ofP. jirovecii, the dihydrofolate synthase (dhfs) and the aminodeoxychorismate lyase (abz2). The function of these enzymes was demonstrated by the rescue of the null allele of the orthologous gene ofSaccharomyces cerevisiae.