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

Abstract

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.

The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks

“…Screening of the Pandemic Response Box has resulted in 11 publications so far. 21 − 31 Such a lag is similar to what was observed for earlier boxes with the peak 2–3 years after launch, as seen in Figure 8 . Throughout 2020 and early 2021, the pandemic has shifted research, with a focus on SARS-CoV2, impacting the number and delaying publications.…”

Screening of the Medicines for Malaria Venture Pandemic Response Box for Discovery of Antivirulent Drug against Pseudomonas aeruginosa

“…Our data provide an overview of one of the first approaches taken to use bioactive compound data sets such as the PRB and for repurposing known compounds and development of a drug with antivirulent potential. Together with other such efforts ( 18 , 23 , 24 ), our study shows the versatility of PRB-like compound data sets and the power of drug-repurposing strategies to combat AMR development as well as possibly other sudden medical emergencies. Well-described drug metabolism and pharmacokinetics (DMPK) profiles will provide an additional advantage for these compounds to rapidly progress through the drug discovery pipeline ( 18 ).…”

Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species

“…Some of these compounds were described as exhibiting activity against other fungi. MMV1634491 showed in vitro antifungal activity against mycetoma agents and improved the survival rate of Galleria mellonella infected with Madurella mycetomatis , as well as the compound MMV019724 (previously described as an antiviral molecule [ 10 ]) [ 22 ]. MMV019724 inhibited the fungal growth of Cryptococcus spp.…”