S6.5c MycetOS: identifying drugs which can penetrate the mycetoma grain

Abstract

S6.5 Efforts of improving the management of mycetoma: working towards the 2030 goals, September 22, 2022, 4:45 PM - 6:15 PMMycetoma is a neglected tropical disease characterized by large subcutaneous swellings and the formation of grains. Madurella mycetomatis is the most common causative agent. Currently, mycetoma is treated with a combination of itraconazole therapy and surgery with low success rates, resulting often in amputation and social sigma. To improve the current therapeutic success rates a novel drug is needed. Due to the lack of interest in the pharmaceutical industry, an open-source drug discovery program for mycetoma was established called MycetOS. In total 1360 compounds were screened for in vitro activity against M. mycetomatis, and many more are currently being screened. Compounds that were able to inhibit growth at 100 μm, 25 μm, and had an IC50 <8 μm were selected for studying the in vivo efficacy in an M. mycetomatis grain model in the invertebrate Galleria mellonella. Out of the 1360 compounds screened against M. mycetomatis, 302 were able to inhibit growth at 100 μm, and 23 of those met all criteria to be screened in vivo. Of these 23, nine did prolong larval survival. These included 3/7 azoles tested, olorofim, fenbendazole, MMV006357, MMV022478, MMV675968, and MMV1782387. Based on these results, 6 compound series were selected for further studying, these included the fenarimols (series 1), the aminothiazoles (series 2), the phenotiazines (series 3), dihydrofolate reductase inhibitors (series 4), benzimidazoles (series 5) and the ketoximines (series 6). For series 1 in total 185 additional compounds were screened. By analyzing the in vitro activity and in vivo efficacy in relation to the chemical properties of the molecules it appears that the LogD value of a compound was important for penetrating into the mycetoma grain. In conclusion, using an open source drug discovery approach for mycetoma we were able to identify novel lead compounds. Some of these compounds were highly active against M. mycetomatis only (fenarimols, aminothiazoles, phenotiazines, and ketoximines), while other compounds such as the benzimidazoles also were active against other causative agents as well. Screening more analogs of identified compounds allowed us also to identify chemical properties which are favorable for grain penetration in vivo. This will allow us to chemically design more active compounds for this difficult to treat infection.