Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Abstract

AbstractEumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungusMadurella 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 activein 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 theirin vitroactivity againstM. mycetomatishyphae, rendering four further hit compounds. To assess thein vivopotency of these hit compounds, aGalleria mellonellalarvae model infected withM. mycetomatiswas used. Several of the compounds identifiedin vitrodemonstrated promising efficacyin vivoin terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of anOpen 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.Author summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungusMadurella mycetomatis.Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity againstM. mycetomatisin vitro and several in vivo with ourGalleria mellonellalarvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.