Melanin biosynthesis in Madurella mycetomatis and its effect on susceptibility to itraconazole and ketoconazole.

One of the hallmarks of eumycetoma is the formation of fungal grains, which are secreted by multiple sinuses in infected tissues. Madurella mycetomatis grains are black. This black colour was shown to be due to the presence of melanin. Melanin can be produced through various biochemical pathways. It appeared that M. mycetomatis melanisation could be blocked by inhibitors of the pyo- and dihydroxynaphthalene (DHN)-melanin pathways but not by inhibitors of the dihydroxyphenylalanine (L-DOPA)-melanin pathway. Melanin isolated from M. mycetomatis cells provides in vitro protection against the killing effects of the oxidant permanganate and several antifungals. When melanin was added to the culture medium, MICs were found to be 16-fold elevated in the case of itraconazole and 32-fold for ketoconazole. MICs for amphotericin B, fluconazole and voriconazole were not affected. Since itraconazole and ketoconazole are the main antifungal agents used to treat mycetoma, the clinical relevance of the in vitro rise in MIC should be studied further.