Biology of NAD+-dependent lysine deacetylases (Sirtuins) in Aspergillus fumigatus

• Grant number: 20/06151-4
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2020 - February 28, 2023
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: André Ricardo de Lima Damasio
• Grantee: André Ricardo de Lima Damasio
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Antonello Mai ; Dante Rotili ; Nilmar Silvio Moretti ; Rino Ragno
• Associated scholarship(s): 21/11475-6 - Screening of synthetic lysine deacetylases inhibitors active against A. fumigatus, BP.TT

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, azole, echinocandins and amphotericin B, 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). 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. This fact suggests that KATs and KDACs can be potentially targeted for use in combination with azoles for the treatment of A. fumigatus azole-resistant strains. The aim of this study is to evaluate the potential of KDAC inhibitors in the A. fumigatus growth, to describe the acetylome (set of acetylated proteins) of A. fumigatus Af293 (reference strain) and A. fumigatus LIF 2552-4.957 (azole-resistant strain), and to evaluate the virulence of A. fumigatus after deletion of sirtuin-encoding genes. (AU)