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.

Candida albicans increases the pathogenicity of Staphylococcus aureus during polymicrobial infection of Galleria mellonella larvae

“…Advances in technologies associated with the detection of these microbes will eventually enter the clinic and this will require the reclassification of many mono-infections as polymicrobial infections. The work presented here aimed to develop an in vivo system to study the pathogenesis of polymicrobial infection using G. mellonella larvae, which have been widely used for studying the development of single-species infections [46–49].…”

A Highly Active Triterpene Derivative Capable of Biofilm Damage to Control Cryptococcus spp.

“…Larval survival was monitored for 10 days. Insignificant differences in larval survival between the treated group and the control group indicated a lack of toxicity [27].…”

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

“…[32,33,[45][46][47][48][49][50][51], Aspergillus spp. [13,29,35,[52][53][54][55][56][57][58][59][60][61], Mucorales [62][63][64], Madurella mycetomatis [65][66][67], and other fungal agents [68][69][70]. The contribution of G. mellonella to the evaluation of antifungal drugs will be detailed in the following paragraphs.…”

“…G. mellonella has also been used to test new drugs against M. mycetomatis [67]. After the in vitro screening of 800 molecules, the 10 most potent compounds were tested in vivo in G. mellonella.…”

“…In particular, a fenarimol analogue, a non-azole Cyp51 inhibitor, showed promising results. Based on these results, several other fenarimol analogues were also tested in G. mellonella model [67].…”