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Published on: November 8, 2006
Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal
Norman van Rhijn1, Can Zhao1, Narjes Al-Furaiji1,2
1Manchester Fungal Infection Group, Division of Evolution, Infection and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Abstract:
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.
Insights
Inhibiting the Aspergillus fumigatus YakA kinase with 1-ECBC enhances azole antifungal efficacy. This combination reduces fungal pathogenicity and improves treatment outcomes for lung infections.
Area of Science:
- Medical Mycology
- Molecular Biology
- Drug Discovery
Background:
- * *Aspergillus fumigatus* is a pathogenic fungus causing over 10 million lung disease cases annually.
- * Azole antifungals are first-line treatments, but rising resistance necessitates novel therapeutic strategies.
- * Identifying synergistic targets with azoles is crucial for improving treatment outcomes.
Purpose of the Study:
- * To identify novel antifungal targets that synergize with azole antifungals.
- * To investigate the role of protein kinase YakA in *A. fumigatus* pathogenicity and azole susceptibility.
- * To evaluate the efficacy of 1-ethoxycarbonyl-beta-carboline (1-ECBC) in combination with azoles.
Main Methods:
- * Generation of a library of 111 barcoded null mutants in *A. fumigatus* protein kinase genes.
- * Phenotypic analysis of kinase deletion mutants for azole hypersensitivity and pathogenicity.
- * Assessment of YakA's role in stress response and fungal invasion.
- * Testing the synergistic effect of 1-ECBC with azoles against *A. fumigatus*.
Main Results:
- * Deletion of the YakA kinase gene resulted in hypersensitivity to azoles and reduced pathogenicity.
- * YakA regulates septal pore blocking in response to stress in *A. fumigatus*.
- * Loss of YakA impairs fungal growth in solid media and *in vivo* mouse lung models.
- * 1-ECBC inhibits stress-mediated septal pore blocking and synergizes with azoles to inhibit fungal growth.
Conclusions:
- * YakA is a key regulator of stress response and pathogenicity in *A. fumigatus*.
- * Targeting YakA with 1-ECBC offers a promising strategy to overcome azole resistance.
- * Combination therapy of azoles and 1-ECBC could improve treatment of invasive aspergillosis.
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