Kinome analysis of Madurella mycetomatis identified kinases in the cell wall integrity pathway as novel potential therapeutic drug targets in eumycetoma caused by Madurella mycetomatis

Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Currently, eumycetoma is treated by a combination of antifungal therapy and surgery, with limited success rates. To identify novel drug targets we used an in silico approach to determine...

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Vydáno v:PLoS neglected tropical diseases Ročník 19; číslo 9; s. e0013482
Hlavní autoři: Konings, Mickey, Strepis, Nikolaos, Manabe, Ri-Ichiroh, Hasegawa, Akira, Chaudhari, Somdatta, du Pré, Saskia, Schippers, Marij, Tagami, Michihira, Ma, Jingyi, Okazaki, Yasushi, Todd, Matthew, Biersack, Bernhard, Masand, Vijay, Verbon, Annelies, Kasukawa, Takeya, Abugessaisa, Imad, van de Sande, Wendy W. J.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 01.09.2025
Public Library of Science (PLoS)
Témata:
Animals
Antifungal agents
Antifungal Agents - pharmacology
Antimicrobial agents
Cell Wall - drug effects
Cell Wall - enzymology
Cell Wall - metabolism
Cell walls
Datasets
Drug development
Drugs
Fungal Proteins - genetics
Fungal Proteins - metabolism
Fungi
Fungicides
Gene expression
Genomes
Humans
Infections
Integrity
Kinases
Madurella - drug effects
Madurella - enzymology
Madurella - genetics
Madurella mycetomatis
Moths - microbiology
Mycetoma - drug therapy
Mycetoma - microbiology
Phosphotransferases - genetics
Phosphotransferases - metabolism
Protein Kinase Inhibitors - pharmacology
Proteins
Signal Transduction
Therapeutic targets
Tropical diseases
Netherlands
ISSN:1935-2735, 1935-2727, 1935-2735
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Popis
Shrnutí:Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Currently, eumycetoma is treated by a combination of antifungal therapy and surgery, with limited success rates. To identify novel drug targets we used an in silico approach to determine the kinases present in M. mycetomatis genome and rank them as potential drug targets. In total 132 predicted kinases were identified in M. mycetomatis , of which 21 were predicted to be essential for fungal viability and 4 of these had no human orthologues. Two were linked to the Cell Wall Integrity (CWI) signalling pathway and were expressed in a Galleria mellonella infection model. Several kinase inhibitors were identified after in silico modelling, however only 8 were able to inhibit growth. Five had predicted binding affinity with components of the CWI. Altogether, the CWI shows potential as a drug target for further evaluation.
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ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0013482