title: Functional characterization of the Pneumocystis jirovecii potential drug targets dhfs and abz2 involved in folate biosynthesis.
abstract: Pneumocystis species are fungal parasites colonizing mammal lungs with strict host specificity. Pneumocystis jirovecii is 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 the P. jirovecii genome 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 model Pneumocystis 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 of P. 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 of Saccharomyces cerevisiae.
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Luraschi
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: O H
authors.initials: OH
authors.lastname: Cissé
authors.affiliation: Service of Dermatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Monod
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Pagni
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland Philippe.Hauser@chuv.ch.
authors.forename: P M
authors.initials: PM
authors.lastname: Hauser
mesh_terms: D005492:Folic Acid / Q000096:biosynthesis* / Q000378:metabolism; D016681:Genome, Fungal / Q000235:genetics; D007652:Oxo-Acid-Lyases / Q000235:genetics / Q000378:metabolism; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D045363:Pneumocystis carinii / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D005492:Folic Acid; D007652:Oxo-Acid-Lyases; C066600:aminodeoxychorismate lyase; D010453:Peptide Synthases; C020041:dihydrofolate synthetase