Lim, W;
Melse, Y;
Konings, M;
Hung, PD;
Eadie, K;
Laleu, B;
Perry, B;
... van de Sande, WWJ; + view all
(2018)
Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma.
PLoS Neglected Tropical Diseases
, 12
(4)
, Article e0006437. 10.1371/journal.pntd.0006437.
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Abstract
Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.
| Type: | Article |
|---|---|
| Title: | Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pntd.0006437 |
| Publisher version: | https://doi.org/10.1371/journal.pntd.0006437 |
| Language: | English |
| Additional information: | © 2018 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | Larvae, Fungal pathogens, Antifungals, Drug research and development, Fungal diseases, Fungi, Library screening |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10057219 |
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