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

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.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 fungus Madurella 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 against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae 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.

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

“…To discover new drug candidates to treat mycetoma, we have previously tested 800 compounds from the Pathogen Box and Stasis Box obtained from Medicines for Malaria Venture (MMV) for activity against M. mycetomatis [10]. These compound libraries contained druglike molecules previously shown to be active against pathogens causing tropical and neglected diseases (Pathogen Box) or candidates that had been studied in clinical studies and could, thus be potentially repurposed for neglected diseases (Stasis Box).…”

“…In return, researchers were asked to share their findings in the public domain, creating an open and collaborative forum for infectious disease drug research. Out of 800 compounds screened, we discovered 215 compounds that were able to inhibit M. mycetomatis growth at a concentration of 100 μM in vitro and five that were able to prolong larvae survival in an in vivo Galleria mellonella wax moth model [10]. That resulted in the discovery of fenarimols as a potential new class of antifungal compounds able to inhibit M. mycetomatis growth both in vitro and in vivo [10].…”

“…Out of 800 compounds screened, we discovered 215 compounds that were able to inhibit M. mycetomatis growth at a concentration of 100 μM in vitro and five that were able to prolong larvae survival in an in vivo Galleria mellonella wax moth model [10]. That resulted in the discovery of fenarimols as a potential new class of antifungal compounds able to inhibit M. mycetomatis growth both in vitro and in vivo [10]. Eumycetoma however, can also be caused by fungi other than M. mycetomatis, therefore, it is crucial to know if these compounds can also inhibit other common causative agents of mycetoma.…”

Treatment of refractory mycetoma by radiotherapy: a case study and review

“…Still, the cure rate is around 30%. The MycetOS (Mycetoma Open Source) project was launched to discover new drugs to find a cure for this debilitating disease 28 . In this medically problematic situation, in particular, in cases where the amputation of the foot is considered, other treatment approaches, such as RT, are justified.…”

Screening the MMV Open Access Pathogen box unveils novel and potent inhibitors of Amoebiasis agent: Entamoeba histolytica

“…This compound was also identified as a dual hit of Cryptosporidium parvum and Giardia lamblia with 88% and 90% inhibition respectively in the initial screen of the box compounds by Hennessey et al [48]. Another study by Lim et al [53] has found compound 1 among the 13 most potent MMV Pathogen Box compounds against Madurella mycetomatis , a fungus primarily reported in Central Africa as the causative agent of mycetoma in humans, which is a chronic infectious and inflammatory disease. Beyond the numerous activities reported of compound MMV675968, it was also showed in this study to be active against E. histolytica with IC 50 of 2.10µM, rationally inhibiting the amoebal DHFR enzyme as suggested by the findings of Lau et al [50].…”