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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

Summary

Eumycetoma is a serious fungal infection that causes large skin lesions and is very difficult to treat, even with long-term medication and surgery. Researchers used computer analysis to identify proteins called kinases that are essential for the fungus to survive. They found that targeting kinases involved in building the fungal cell wall could potentially lead to new treatments. By testing existing drugs, they discovered eight compounds that could inhibit fungal growth, offering hope for better treatment options.

Background

Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Current treatment combines antifungal therapy with surgery but has limited success rates. Novel drug targets are needed to improve therapeutic outcomes.

Objective

To identify M. mycetomatis-specific kinases as potential drug targets using in silico approaches, genomic comparison, and transcriptomic analysis. The study aimed to characterize kinases in the cell wall integrity pathway and evaluate kinase inhibitors for their ability to inhibit fungal growth.

Results

Twenty-one kinases were predicted as essential for fungal viability, with four having no human orthologues. Two kinases (MMYC01_208733 and MMYC01_207542) linked to the Cell Wall Integrity pathway were expressed during infection. Molecular docking identified eight kinase inhibitors with predicted binding affinity to pathway components.

Conclusion

The Cell Wall Integrity signaling pathway shows potential as a drug target for eumycetoma treatment. Several kinase inhibitors demonstrated in vitro activity against M. mycetomatis, warranting further evaluation as lead compounds for drug development in the MycetOS program.
  • Published in:PLoS Neglected Tropical Diseases,
  • Study Type:Bioinformatics Analysis, In Silico and In Vitro Study,
  • Source: PMID: 40906790, DOI: 10.1371/journal.pntd.0013482
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