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Study of the resistance of Fusarium and Aspergillus clinical isolates to azole antifungals and the biosynthesis of metallic nanoparticles as an antifungal therapeutic alternative.

Grant number: 23/12463-7
Support Opportunities:Regular Research Grants
Duration: May 01, 2024 - April 30, 2026
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal Investigator:Marcia Regina von Zeska Kress
Grantee:Marcia Regina von Zeska Kress
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers: Adriana Rodrigues Alves ; Cledir Rodrigues Santos ; Eliana Guedes Stehling ; Glaucia Rigotto Caruso ; Márcia Eliana da Silva Ferreira ; Nelson Manuel Viana da Silva Lima ; Otávio Guilherme Gonçalves de Almeida ; Priscyla Daniely Marcato Gaspari

Abstract

The fungal genera Fusarium and Aspergillus present species that cause severe infections, mainly in immunosuppressed patients. In addition, attention has been drawn to the gradual increase in the frequency of resistance to antifungals. Resistance to azoles is a complex public health challenge. In 2022, the World Health Organization (WHO) classified Fusarium spp. and Aspergillus fumigatus among the pathogens in the high and critical priority groups, respectively, in response to their involvement in the growing threat of fungal infections and consequent high perceived importance to public health.The main species of the F. solani and F. oxysporum complexes investigated by our research group are F. solani, F. petroliphilum, F. keratoplasticum, F. falciforme, and F. oxysporum, in addition to other species from other species complexes such as F. proliferatum, F. sacchari, and F. delphinoides. Furthermore, our research group studies clinical species isolates from the Fumigati and Flavi sections (A. fumigatus s.s., A. flavus, A. parasiticus, and A. tamarii). These studies showed that azole resistance is not exclusive to a single factor. In this sense, we propose in this project the search for biomarkers involved in resistance to azoles through the analysis of transcriptomes of clinical isolates of Aspergillus spp. and mainly for Fusarium spp., still little explored in this area. Some genetic determinants will be selected for expression validation by qPCR and the influence on susceptibility to antifungals by gene deletion in Aspergillus fumigatus.Few complete genomes with known MIC of azole antifungals from clinical isolates of Fusarium spp. are available. Thus, this project proposes sequencing clinical isolates of Fusarium spp. and Aspergillus spp. with high and low azoles MIC. The respective complete genomes will be annotated and will help in transcriptomic analyses. Data generated in transcriptomics will be investigated in the genome of different clinical isolates. Thus, possible resistance biomarkers shared by Fusarium and Aspergillus genera or belonging to each one will be identified. These could be potential therapeutic targets to increase the repertoire of therapeutic options and, consequently, a more efficient antifungal therapy.Concerning the emergence of fungal resistance to commercial drugs, it is necessary to discover new molecules and antimicrobial treatments to combat these infections. Extremophile fungi from Antarctica have been explored as potential sources of bioactive compounds capable of acting as antimicrobials. On the other hand, nanotechnology also explores antimicrobial activity and ways of delivering bioactive compounds to increase treatment efficiency. Metallic nanoparticles are highlighted as drug carriers due to their unique surface-enhancing and biocompatibility properties. Thus, we propose to explore fungi from Antarctica as "biofactories" for the biosynthesis of metallic nanoparticles. We seek to investigate biological activities emphasizing antifungal activity as a new therapeutic alternative for fungal infections. (AU)

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