2026-07-21T08:48:46Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/262612025-12-18T12:59:58Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc van Rhijn, Norman author Zhao, Can author Al-Furaiji, Narjes author Storer, Isabelle S R author Valero, Clara author Gago, Sara author Chown, Harry author Baldin, Clara author Grant, Rachael-Fortune author Bin Shuraym, Hajer author Ivanova, Lia author Kniemeyer, Olaf author Krüger, Thomas author Bignell, Elaine author Goldman, Gustavo H author Amich, Jorge author Delneri, Daniela author Bowyer, Paul author Brakhage, Axel A author Haas, Hubertus author Bromley, Michael J author 2024-06-11 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. van Rhijn N, Zhao C, Al-Furaiji N, Storer ISR, Valero C, Gago S, Chown H, Baldin C, Grant RF, Bin Shuraym H, Ivanova L, Kniemeyer O, Krüger T, Bignell E, Goldman GH, Amich J, Delneri D, Bowyer P, Brakhage AA, Haas H, Bromley MJ. Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging. Nat Commun. 2024 Jun 11;15(1):4984. 10.1038/s41467-024-48592-8 2041-1723 Nature communications 38862481 https://hdl.handle.net/20.500.12105/26261 Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.