Analysis of Current Antifungal Agents and Their Targets within the Pneumocystis carinii Genome

Aleksey      Porollo; Jaroslaw      Meller; Yogesh      Joshi; Vikash      Jaiswal; A.      George Smulian; Melanie      T. Cushion

Abstract

Pneumocystis pneumonia (PCP) remains a leading opportunistic infection in patients with weakened immune systems. The fungus causing the infection belongs to the genus, Pneumocystis, and its members are found in a large variety of mammals. Adaptation to the lung environment of a host with an intact immune system has been a key to its successful survival. Unfortunately, the metabolic strategies used by these fungi to grow and survive in this context are largely unknown. There were considerable impediments to standard approaches for investigation of this unique pathogen, the most problematic being the lack of a long term in vitro culture system. The absence of an ex vivo cultivation method remains today, and many fundamental scientific questions about the basic biology, metabolism, and life cycle of Pneumocystis are unanswered. Recent progress in sequencing of the Pneumocystis carinii genome, a species infecting rats, permitted a more informative search for genes and biological pathways within this pathogen that are known to be targets for existing antifungal agents. In this work, we review the classes of antifungal drugs with respect to their potential applicability to the treatment of PCP. Classes covered in the review are the azoles, polyenes, allylamines, and echinocandins. Factors limiting the use of standard antifungal treatments and the currently available alternatives (trimethoprim-sulfamethoxazole, atovaquone, and pentamidine) are discussed. A summary of genomic sequences within Pneumocystis carinii associated with the corresponding targeted biological pathways is provided. All sequences are available via the Pneumocystis Genome Project at http://pgp.cchmc.org/.

Keywords: Antifungal agents, Antifungal drug resistance, Antifungal drug targets, Pneumocystis biological pathways, Pneumocystisgenome project, Pneumocystis pneumonia, trimethoprim-sulfamethoxazole, atovaquone, pentamidine, immune system.