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 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.
Authors
- Mickey Konings (ORCID: https://orcid.org/0000-0003-3983-4304)
- Imad Abugessaisa (ORCID: https://orcid.org/0000-0001-7458-801X)
- Vijay Hariram Masand (ORCID: https://orcid.org/0000-0001-9300-4147)
- Michihira Tagami (ORCID: https://orcid.org/0000-0002-9713-3576)
- Annelies Verbon (ORCID: https://orcid.org/0000-0003-2242-8342)
- Somdatta Chaudhari
- Takeya Kasukawa (ORCID: https://orcid.org/0000-0001-5085-0802)
- Nikolaos Strepis (ORCID: https://orcid.org/0000-0002-0997-8430)
- Yasushi Okazaki (ORCID: https://orcid.org/0000-0003-3241-5502)
- Matthew H. Todd (ORCID: https://orcid.org/0000-0001-7096-4751)
- Wendy W. J. van de Sande (ORCID: https://orcid.org/0000-0002-8652-8783)
- Ri‐Ichiroh Manabe (ORCID: https://orcid.org/0000-0002-4785-4228)
- Bernhard Biersack (ORCID: https://orcid.org/0000-0001-7305-346X)
- Jingyi Ma (ORCID: https://orcid.org/0000-0002-3906-2239)
- Saskia du Pré (ORCID: https://orcid.org/0000-0003-0996-9806)
- Akira Hasegawa (ORCID: https://orcid.org/0000-0002-7674-6955)
- Marij Schippers
Institutions
- Osaka Gakuin University (JP)
- Utrecht University (NL)
- Erasmus MC (NL)
- University Medical Center Utrecht (NL)
- Genomics England (GB)
- RIKEN Center for Integrative Medical Sciences (JP)
- Hindu College of Pharmacy (IN)
- University College London (GB)
- University of Bayreuth (DE)
- The University of Osaka (JP)
Publication Details
- Journal
- PLoS neglected tropical diseases
- Published
- 2025-09-04
- DOI
- https://doi.org/10.1371/journal.pntd.0013482
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministry of Education, Culture, Sports, Science and Technology
- ZonMw
- Erasmus Universiteit Rotterdam
- Drugs for Neglected Diseases initiative
- Japan Society for the Promotion of Science
- RIKEN