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Resistance study of Fusarium spp. clinical isolates to amphotericin B and azoles

Grant number: 20/07546-2
Support type:Regular Research Grants
Duration: June 01, 2021 - May 31, 2023
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Cooperation agreement: Universidad de la Frontera
Principal researcher:Marcia Regina von Zeska Kress
Grantee:Marcia Regina von Zeska Kress
Principal researcher abroad: Cledir Rodrigues Santos
Institution abroad: Universidad de La Frontera (UFRO), Chile
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers: Luis Salazar Navarrete ; Nathalia Baptista Dias

Abstract

In recent years, Fusarium spp. gained importance in human health due to the increasing incidence of fungal infections related to immunosuppressed patients. Fusariosis is the second most common filamentous fungal infection in patients with hematologic neoplasms. Despite advances in therapy and early diagnosis, invasive fusariosis remains associated with high morbidity and up to 70% mortality. In addition, fusariosis affects immunocompetent patients by causing ocular (keratitis) and nail (onychomycosis) infections. Currently, clinically relevant members of Fusarium genera show a high degree of intrinsic resistance to a wide spectrum of commonly used antifungals. The molecular mechanism of such intrinsic resistance is unknown and this resistance renders a challenging treatment and results in high mortality rates in patient population. The main aim of the present project is to study the resistance mechanisms of Fusarium spp. clinical isolates to amphotericin B (AMB) and azoles. In this context, the accuracy of MALDITOF MS (Matrixassisted laser desorption/ionization timeofflight mass spectrometry) minimal profile change concentration (MPCC) will be assessed and compared with results obtained from the classical minimal inhibitory concentration (MIC) assay of 108 Fusarium spp. clinical isolates and for the antifungals AMB, voriconazole (VOR), itraconazole (ITR), terbinafine (TER), and Ciclopirox (CXO). In order to investigate the Fusarium spp. resistance to AMB and Azoles, the antifungal degradation patterns will be evaluated for their chemical structural elucidation by MALDI-TOF MS on the presence of Fusarium spp. clinical isolates. Preliminary experiments for elucidate the degradation patterns of AMB and Azoles molecules in the presence of Fusarium spp. has been developed by MALDI-TOF MS through a collaboration between the Research Groups of Dr. Marcia Regina von Zeska Kress (Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil) and Dr. Cledir Santos (Universidad de La Frontera, Chile). According to the preliminary results, it was observed a degradation pattern of AMB molecule in the presence of Fusarium spp. suggesting a possible enzymatic process of resistance. Thus, secreted enzymes during the exposition of Fusarium spp. clinical isolates to AMB will be assessed by SDS-PAGE electrophoresis and mass spectrometry. The potential enzymes will be analysed by in silico approach. In order to study the intrinsic mechanism of resistance to azoles, mutation in the CYP51 genes from Fusarium spp. clinical isolates resistant to azoles will be sequenced. Finally, the expression level of CYP51 gene from Fusarium spp. clinical isolates resistant to azoles in the presence of azole antifungal will be assessed. As the project main outcome, it is expected to obtain a clear overview on the intrinsic resistance mechanism of Fusarium spp. to AMB and azoles. The results and knowledge obtained with the development of this project will generate information and support for the development of new antifungals and / or the molecular improvement of the compounds currently used. The knowledge of the resistance mechanisms of Fusarium spp. may contribute to the better management and treatment of the infection caused by these fungi. (AU)

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