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van Rhijn, Norman ; Zhao, Can ; Al-Furaji, Narjes ; Storer, Isabelle S. R. ; Valero, Clara ; Gago, Sara ; Chown, Harry ; Baldin, Clara ; Grant, Rachael-Fortune ; Bin Shuraym, Hajer ; Ivanova, Lia ; Kniemeyer, Olaf ; Krueger, Thomas ; Bignell, Elaine ; Goldman, Gustavo H. ; Amich, Jorge ; Delneri, Daniela ; Bowyer, Paul ; Brakhage, Axel A. ; Haas, Hubertus ; Bromley, Michael J.

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 15, n. 1, p. 16-pg., 2024-06-11.

Resumo

More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth. (AU)

• Processo FAPESP: 21/04977-5 - A identificação de vias metabólicas e compostos químicos que podem potenciar a ação de caspofungin contra Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 20/01131-5 - Identificação de novos genes envolvidos em resposta ao estresse em Aspergillus fumigatus através de screening quantitativo de código de barra genético
• Beneficiário: Clara Isabel Valero Fernández
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 18/00715-3 - Caracterização molecular de fatores de transcrição envolvidos no metabolismo de cálcio em Aspergillus fumigatus.
• Beneficiário: Clara Isabel Valero Fernández
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado