Investigation of the mechanisms of persistence and evolution of vorizonazole resistance in serial isolates obtained from the same human patient

• Grant number: 22/09882-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2023
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Laís Pontes
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Aspergillus fumigatus is the main causative agent of Invasive Aspergillosis (IA), which is considered a serious disease with a high mortality rate, especially in immunocompromised patients. The first drug for treatment is Voriconazole (VRC), which belongs to the azole class. Patients undergoing treatment for AI with VRC are at great risk of A.fumigatus undergoing genetic alterations, which can lead to resistance to the antifungal agent. Recently, with the indiscriminate use of antifungals in agriculture and in the clinic, cases of A. fumigatus resistant and persistent to azoles have been increasingly described worldwide. Thus, it becomes necessary to search for the genes involved in this persistence mechanism. Furthermore, in developing countries such as Brazil, where azoles remain the main antifungals in use, investigating the development of tolerance, in addition to resistance, may be especially relevant to predict clinical outcomes that can significantly affect the effectiveness of treatment. This work will be carried out using eight A.fumigatus isolates from a patient with IA who underwent prolonged treatment with VRC during the years 2014 to 2018. These isolates developed a high rate of persistence to VRC before developing the G448S mutation that led to the resistance. To elucidate these mechanisms, RNASeq and Whole Genome Sequencing will be performed.