Ess1: A pathogenic fungal target for a novel class of broad-spectrum therapeutic agents

Project Summary There is a world-wide need for improved treatment of systemic, life-threatening fungal infections. Current therapies are limited by the small number of approved drugs, toxicities, drug- drug interactions, mode of administration, and growing problems of drug resistance and emerging pathogens. Treatment also suffers from a lack of rapid clinical diagnoses, leading to dependence on broad-spectrum antifungal drugs. Moreover, existing antifungal drug classes target membrane and cell wall integrity, and there is a need to develop drugs against targets with new modes of action. Available evidence suggest Ess1 might be one such target. Ess1 is an essential prolyl isomerase that is highly conserved in fungal pathogens, including Candida albicans and Aspergillus fumigatus, and its mechanism-of-action is complementary in that it does not overlap with targets of existing antifungals. Several small molecule andquot;hitsandquot; that show chemical-genetic interactions with Ess1 mutant cells have been identified, and fungal Ess1 structure differs sufficiently from its human ortholog (Pin1) to suggest that development of selective Ess1 inhibitors is feasible. The specific aims of this Phase I proposal are to (1) validate Ess1 as a druggable target and (2) identify inhibitor scaffolds that are chemically tractable for a andquot;hit to leadandquot; drug development program. The approach will use biochemical and whole-cell assays to test inhibitors against Ess1 and Pin1 enzymes, fungal pathogens, and mammalian cells, and to develop a robust exploratory chemistry program to accomplish these aims. The outcomes will advance this program into hit-to-lead, lead optimization and pre-clinical studies (Phase II). The long-term objective is to develop Ess1 inhibitors into a new class of broad-spectrum antifungal drugs.Project Narrative In January 2020, the NIH Institutes of Allergy and Infectious Diseases gathered leading investigators from around the world to discuss the emergence of a multi-drug resistant pathogen called Candida auris and the global problem of systemic fungal infections. The conference highlighted the critical need to develop new, broad-spectrum antifungal drugs to combat not only Candida auris but other Candida and Aspergillus because of increasing resistance to azole drugs, and growing echinocandin resistance in C. glabrata. This proposal aims to develop small molecule chemical inhibitors against Ess1, a new essential fungal target with a unique mode of action, and to develop these into a new class of broad-spectrum antifungal drug to tackle the problem of emerging and drug-resistant fungal infections.