Analysis of Current Antifungal Agents and Their Targets within the Pneumocystis carinii Genome
Aleksey Porollo, Jaroslaw Meller, Yogesh Joshi, Vikash Jaiswal, A. George Smulian and Melanie T. Cushion
Affiliation: Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, 316 Kettering Lab, Cincinnati, OH 45267-0056, USA.
Keywords: Antifungal agents, Antifungal drug resistance, Antifungal drug targets, Pneumocystis biological pathways, Pneumocystisgenome project, Pneumocystis pneumonia, trimethoprim-sulfamethoxazole, atovaquone, pentamidine, immune system.
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
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