Evaluation of the role of the two-component system in the cell signaling of echinocandin resistant Candida glabrata

• Grant number: 24/03612-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2024
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Sergio Schenkman
• Grantee: Ricardo Ferreira Lima
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/10599-3 - The Antimicrobial Resistance Institute of São Paulo (The Aries Project), AP.CEPID

Abstract

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata. The echinocandins target 1,3-²-glucan synthase (GS), the enzyme responsible for producing 1,3-²-glucans, a major component of the fungal cell wall. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. The two-component system is one of the most important Candida spp. signal transduction pathways, regulating the response to oxidative and osmotic stresses, adhesion, morphogenesis, cell wall synthesis, virulence, drug resistance, and the host-pathogen interactions. The two-component system in eukaryotes involves three proteins: a sensor protein, an intermediate protein and a response regulator, and requires the transfer of a phosphate group between two histidine-aspartic residues. Notably, some components of this signaling pathway have not been found in the human genome, indicating that the two-component system of C. glabrata can be a potential target for new antifungal agents. In this study, we will aim to evaluate the role of two-component system (basically the histidine kinase CgSln1) in echinocandin tolerance in C. glabrata. Finnaly, the characterization of HK and its signaling pathway will serve to better understand the mechanisms involved with the C. glabrata resistant to echinocandins.