Fungal Pathogens Research: Novel and Improved Molecular Approaches for the Discovery of Antifungal Drug Targets

Abstract

With the rise of fungal infection incidence amongst the patient population, the importance of developing new antifungal drug targets is higher than ever. This review mainly focuses on the three most prevalent fungal pathogens, Candida, Aspergillus and Cryptococcus, and on the most recent progresses in molecular research that contribute to a better understanding of the pathogen itself, but also its host and the interaction with its host. We consider the progress made in comparative genomics following the huge effort of fungal genome sequence projects undertaken in the last few years. We focus not only on currently used mammalian animal models such as mice, but also on novel non-mammalian models, such as the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, which offer useful tools in the area of the innate immune response to fungal infections. In addition we relate to the recent genomic and proteomic studies and focus on the use of these approaches in in vivo experiments in the pathogen itself as well as in the host. Finally, we describe the latest targeted mutagenesis strategy available in C. albicans and the use of RNA interference in both Cryptococcus neoformans and A. fumigatus. Our aim is not to give an exhaustive list of all new strategies but rather to give an overview of what will contribute most to the identification of new antifungal drug targets and the establishment of novel antifungal strategies.

Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans

“…Although methods of transformation (spheroplast-polyethylene glycol, lithium acetate, and electroporation) are patterned after those used with S. cerevisiae, the transformation efficiency is poor. For the study of gene function in C. albicans, a number of disruption protocols and selectable markers are commonly utilized (300). The most widely used marker is the URA3 gene, which encodes orotidine-5Ј-phosphate decarboxylase and confers uracil prototrophy.…”

Proteomic Profile of Cryptococcus neoformans Biofilm Reveals Changes in Metabolic Processes

“…10,29 However, information regarding the molecular mechanisms specifically associated with the biofilm formation remains limited. These approaches could provide a framework for the identification of new proteins and pathways associated with fungal pathogenesis and maintenance.…”

Metergoline-induced cell death in Candida krusei

“…Unfortunately, most of these agents have a narrow activity spectrum, poor bioavailability, and poor gastrointestinal absorption. Moreover, prolonged usage leads to toxic effects in kidney and liver (Ghannoum & Rice 1999;Tournu et al 2005). Abuse of these antifungal agents also results in the emergence of resistant strains.…”