Advances in fungal chemical genomics for the discovery of new antifungal agents

Abstract

Invasive fungal infections have escalated from a rare curiosity to a major cause of human mortality around the globe. This is in part due to a scarcity in the number of antifungal drugs available to combat mycotic disease, making the discovery of novel bioactive compounds and determining their mode of action of utmost importance. The development and application of chemical genomic assays using the model yeast Saccharomyces cerevisiae has provided powerful methods to identify the mechanism of action of diverse molecules in a living cell. Furthermore, complementary assays are continually being developed in fungal pathogens, most notably Candida albicans and Cryptococcus neoformans, to elucidate compound mechanism of action directly in the pathogen of interest. Collectively, the suite of chemical genetic assays that have been developed in multiple fungal species enables the identification of candidate drug target genes, as well as genes involved in buffering drug target pathways, and genes involved in general cellular responses to small molecules. In this review, we examine current yeast chemical genomic assays and highlight how such resources provide powerful tools that can be utilized to bolster the antifungal pipeline.

Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets

“…We tested the sensitivity of heterozygous mutants to the translation inhibitor nourseothricin (NAT). This is based on the principle that modifying the expression of a compound target often alters the amount of compound required to inhibit that target 11 , 49 . Drug susceptibility analysis demonstrated that heterozygous mutants for all predicted eIF3 subunits were hypersensitive to NAT (Fig.…”

“…In addition, targeting aminoacyl-tRNA synthetases has been explored to treat infections caused by diverse bacteria and parasites, with the benzoxaborole compound tavaborole being the first aminoacyl-tRNA synthetase inhibitor approved for treatment of microbial infections 74 , 75 . As high-throughput sequencing and chemogenomic approaches continue to advance 11 , 76 , 77 , our ability to rapidly identify compounds predicted to target essential gene products will dramatically improve, catalyzing discovery and development of much-needed treatment options to combat life-threatening fungal disease.…”

“…Essential genes that are fungal-specific or have limited conservation in humans provide attractive targets for selectively killing the pathogen 10 , motivating systematic analysis of genes required for fungal survival to expand the target space for drug development. Functional genomic analyses in the model yeast Saccharomyces cerevisiae have established extensive functional redundancy and buffering, as only ~17% of genes in S. cerevisiae are essential under standard laboratory conditions 11 , 12 . Extrapolation to fungal pathogens is limited as ~40% of C. albicans genes lack identifiable homologs in S. cerevisiae and ~19% of C. albicans predicted proteins display no significant similarity to proteins from other organisms 13 .…”

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

“…In addition to employing non-traditional compound libraries for the discovery of novel antifungals, alternative high-throughput screening platforms that specifically identify fungicidal molecules have been developed 91 , 92 . These platforms, coupled with genetic and proteomic methods to unveil the targets of compounds 93 , 94 , have been instrumental in identifying novel drug targets and efficacious compounds.…”

Unraveling Caspofungin Resistance in Cryptococcus neoformans

“…For more than 3 decades, the identification of fungal pathogenesis factors as new targets, the search for new biological and synthetic compounds with interesting antifungal activities, and deciphering molecular mechanisms involved in primary or acquired resistance toward antifungals have been part of a global strategy for antifungal drug development aiming ultimately at improving the management of deep-seated fungal infections ( 13 , 14 ). Indeed, in the same way as antibiotic resistance in bacterial pathogens—but of course to a lesser extent—antifungal resistance has progressively become a serious clinical issue ( 15 , 16 ).…”