Molecular Approaches to Target Drug Discovery in Human Pathogenic Fungi
Neeraj Chauhan and Richard Calderone
from: Pathogenic Fungi: Insights in Molecular Biology (Edited by: Gioconda San-Blas and Richard A. Calderone). Caister Academic Press, U.K. (2008)
Anti-fungal drug discovery remains a major emphasis in research laboratories since current drugs can be toxic to the patient (amphotericin B) or less toxic but only inhibitory (triazoles) such that resistant strains are selected for during their use in patients. The high mortality and morbidity in patients, as for example, with invasive candidiasis in part is due to the inability to detect the organism. Consequently, empirical use of anti-fungals can offer coverage of the disease but again patients are at risk for the selection of drug resistant strains if triazoles are used. There are two approaches to new drug discovery. First, traditional methods utilize large compound libraries that can be tested against pathogens, gene-manipulated pathogens, or model fungi such as Saccharomyces cerevisiae. Hits are noted and then selected compounds are subjected to a serious scrutiny that includes identifying their specificity, toxicity, and redesigning the compound to increase its killing or reduce its toxicity. These facets are just part of the scheme that industry must fulfill to establish a new drug on the market. The development of molecular biology tools and the availability of whole genome sequences have provided a second recourse to drug discovery. Here, the emphasis has been placed upon the identification of essential genes; that insight is quite clear and easy to accept. If the pathogen requires a protein for its growth, then a drug that targets that protein has the same affect as the lack of that protein hopefully in the context of disease. Better yet, in the absence of that protein, the organism is inviable. In this review, methods will be discussed that provide leads in the race to find essential genes. Molecular biological approaches to this end are common to some fungal pathogens, but less studied in others. Thus, whether or not targets are common to many fungal pathogens, enabling the discovery of broad-based activities of select compounds is now partially addressed read more ...