Effect of synthetic lysine deacetylases (KDACs) inhibitors in Aspergillus fumigatus: potential antifungal drugs

• Grant number: 18/20634-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date until: January 01, 2019
• End date until: August 31, 2020
• 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

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, 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 (KAT and KDAC, respectively) 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 KATs and KDACs. This fact suggests that KAT and KDAC can be potentially new antifungals. Preliminary results indicate that the sirtuins inhibitors nicotinamide, sirtinol, and salermide showed significant effects on the growth reduction of the A. fumigatus Af293 strain. The aim of this study is to analyze the antifungal potential of KADCs inhibitors in invasive aspergillosis caused by A. fumigatus and evaluate the expression profile of KDACs in A. fumigatus azole-resistant strains. (AU)