Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma

Eumycetoma is a chronic subcutaneous neglected tropical disease that can be caused by more than 40 different fungal causative agents. The most common causative agents produce black grains and belong to the fungal orders Sordariales and Pleosporales. The current antifungal agents used to treat eumyce...

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Bibliographic Details
Published in:PLoS neglected tropical diseases Vol. 16; no. 2; p. e0010159
Main Authors: Lim, Wilson, Nyuykonge, Bertrand, Eadie, Kimberly, Konings, Mickey, Smeets, Juli, Fahal, Ahmed, Bonifaz, Alexandro, Todd, Matthew, Perry, Benjamin, Samby, Kirandeep, Burrows, Jeremy, Verbon, Annelies, van de Sande, Wendy
Format: Journal Article
Language:English
Published: United States Public Library of Science 01.02.2022
Public Library of Science (PLoS)
Subjects:
Acetamides - pharmacology
Agents
Amputation
Animals
Antifungal agents
Antifungal Agents - pharmacology
Ascomycota - drug effects
Benzimidazoles
Biology and Life Sciences
Carbamates (tradename)
Carbendazim
Causes of
Diagnosis
Drug development
Drug Discovery
Drug Evaluation, Preclinical
Drug therapy
Drugs
Fenbendazole - pharmacology
Fungal diseases
Fungal infections
Fungi
Fungicides
Growth
Identification and classification
Itraconazole
Larvae
Madurella - drug effects
Malaria
Medicine and Health Sciences
Metabolism
Molecules
Moths - microbiology
Mycetoma - drug therapy
Mycoses
Neglected Diseases
Optimization
Pandemics
Pathogens
Phylogenetics
Physical Sciences
Piperazines - pharmacology
Pyrimidines - pharmacology
Pyrroles - pharmacology
R&D
Ravuconazole
Research & development
Surgery
Survival
Tafenoquine
Terbinafine
Testing
Thiazoles - pharmacology
Triazoles - pharmacology
Tropical climate
Tropical diseases
Netherlands
Mexico
ISSN:1935-2735, 1935-2727, 1935-2735
Online Access:Get full text
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Summary:Eumycetoma is a chronic subcutaneous neglected tropical disease that can be caused by more than 40 different fungal causative agents. The most common causative agents produce black grains and belong to the fungal orders Sordariales and Pleosporales. The current antifungal agents used to treat eumycetoma are itraconazole or terbinafine, however, their cure rates are low. To find novel drugs for eumycetoma, we screened 400 diverse drug-like molecules from the Pandemic Response Box against common eumycetoma causative agents as part of the Open Source Mycetoma initiative (MycetOS). 26 compounds were able to inhibit the growth of Madurella mycetomatis , Madurella pseudomycetomatis and Madurella tropicana , 26 compounds inhibited Falciformispora senegalensis and seven inhibited growth of Medicopsis romeroi in vitro . Four compounds were able to inhibit the growth of all five species of fungi tested. They are the benzimidazole carbamates fenbendazole and carbendazim, the 8-aminoquinolone derivative tafenoquine and MMV1578570. Minimal inhibitory concentrations were then determined for the compounds active against M . mycetomatis . Compounds showing potent activity in vitro were further tested in vivo . Fenbendazole, MMV1782387, ravuconazole and olorofim were able to significantly prolong Galleria mellonella larvae survival and are promising candidates to explore in mycetoma treatment and to also serve as scaffolds for medicinal chemistry optimisation in the search for novel antifungals to treat eumycetoma.
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The authors have declared that no competing interests exist.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0010159