Identification of Aspergillus fumigatus protein kinases and phosphatases important for the anti-fungal drug response

• Grant number: 19/16291-0
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: December 31, 2023
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Agreement: University of Manchester
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Gustavo Henrique Goldman
• Principal researcher abroad: Michael John Bromley
• Institution abroad: University of Manchester, England
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Gustavo Henrique Goldman
• Associated research grant: 17/14159-2 - The role of lactose and acetate metabolism in Aspergillus fumigatus virulence, AP.JP

Abstract

Aspergillus fumigatus is the most important airborne mold pathogen and allergen worldwide. Estimates suggest that over 3 million people have invasive or chronic infections that lead to an excess of 600,000 deaths every year. Only three classes of drugs are currently recommended for the treatment of aspergillosis with the azole class being recommended for primary therapeutic purposes and amphotericin B and the echinocandins for salvage therapy. It is of great concern however, that drug resistance to the azoles is rapidly emerging. The mechanism driving resistance in over 50% of strains is unknown and not directly attributable to the modification of the drug target Cyp51A. Understanding the mechanisms that lead to azole resistance would facilitate the rapid detection of resistance and the development of agents that can potentiate azole action. Enzymes such as protein kinases (PK) and protein phosphatases (PP) are known to regulate the development of the cell wall and membrane-targeted by key antifungals. Although over 200 of these enzymes exist, our knowledge of their roles is restricted to only a small subset of these. This project, therefore, proposes to screen an extant mutant library to identify protein kinases and phosphatases whose loss of function results in the potentiation of azole action in A. fumigatus. We will similarly assess the library for potentiators of other antifungals that are either used clinically or those that target pathways that have been proposed as drug targets. This project brings together expertise in high-throughput mutant generation and screening at UoM, with a group at USP that has extensive experience uncovering the functional roles of protein kinase and protein phosphatases in A. fumigatus. Ultimately this project will permit the establishment of further research initiatives between the two centres and generate significant pilot data to advance the development of novel approaches to detect and combat fungal drug resistance. (AU)