The role of NAD+-dependent lysine deacetylases (sirtuin) and their inhibitors in Aspergillus fumigatus acetylome and virulence

• Grant number: 20/01601-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2020
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: André Ricardo de Lima Damasio
• Grantee: Natália Sayuri Wassano
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 23/01824-9 - Investigating secondary metabolites regulated by Sirtuin E (SirE) in Aspergillus fumigatus, BE.EP.DD

Abstract

In the past few years, invasive fungal infections have been among the major causes of mortality and morbidity in immunocompromised individuals. One and a half million deaths are estimated per year, being the Aspergillus fumigatus the main invasive Aspergillosis agent. Characteristics such as morphogenetic changes, host adaptation, and antifungals resistance contribute to the fungus virulence. Isolates resistant to the main drugs used for the Aspergillosis treatment, as azoles and echinocandins, have often been reported. Studies indicate that changes in chromatin, essential for cellular adaptation to physiological and environmental changes, caused by histone lysine acetylation and deacetylation may act to control virulence and drug resistance characteristics. Moreover, several other non-histone proteins from different organisms involved in different biological processes, as oxidative stress response and metabolism, have been described to be acetylated, which are also targets for lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). This fact suggests that KAT and KDAC can be potentially targeted for new antifungals. Preliminary results indicate that the sirtuin (KDAC class III) inhibitors nicotinamide, sirtinol, and salermide showed significant effects on the growth reduction of the A. fumigatus Af293 strain. The aim of this study is describe the acetylome of A. fumigatus sensible and azole-resistant strain in the presence and absence of KDAC inhibitor. In addition, evaluate the phenotype and virulence of A. fumigatus after deletion of sirtuin genes to understand their function and potential as new drug targets. (AU)