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Novel Compound MMV1804559 from the Global Health Priority Box Exhibits In Vitro and In Vivo Activity against Madurella mycetomatis

  • MA Jingyi
  • , Kimberly Eadie
  • , Marthe Schippers
  • , Ahmed H. Fahal
  • , Benoît Laleu
  • , Annelies Verbon
  • , Wendy van de Sande*
  • *Corresponding author for this work
  • Mycetoma Research Center
  • MMV Medicines for Malaria Venture

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
28 Downloads (Pure)

Abstract

Objectives: Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma. Methods: A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely Madurella mycetomatis and Falciformispora senegalensis, and the resulting IC50 and MIC50 values were obtained. Compounds with an IC50 < 8 µM were identified for possible in vivo efficacy studies using an M. mycetomatis grain model in Galleria mellonella larvae. Results: Out of the 400 compounds, 22 were able to inhibit both M. mycetomatis and F. senegalensis growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of M. mycetomatis-infected G. mellonella larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group. Conclusion: MMV1804559 shows promising in vitro and in vivo activity against M. mycetomatis.
Original languageEnglish
Article number6227
JournalInternational Journal of Molecular Sciences
Volume25
Issue number11
DOIs
Publication statusPublished - 5 Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

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