New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole

Abstract

BACKGROUND Black fungi of the Herpotrichiellaceae family are agents of chromoblastomycosis and phaeohyphomycosis. There are few therapeutic options for these infections and it is common to associate antifungal drugs in their treatment. OBJECTIVES To investigate the Medicines for Malaria Venture (MMV) Pathogen Box ® for possible compounds presenting synergism with antifungal drugs used to treat black fungal infections. METHODS An initial screening of the Pathogen Box ® compounds was performed in combination with itraconazole or terbinafine at sub-inhibitory concentrations against Fonsecaea pedrosoi . Hits were further tested against eight Herpotrichiellaceae using the checkerboard method. FINDINGS No synergism was observed with terbinafine. MMV687273 (SQ109) and MMV688415 showed synergism with itraconazole against F. pedrosoi . Synergism of these compounds was confirmed with some black fungi by the checkerboard method. SQ109 and itraconazole presented synergism for Exophiala dermatitidis , F. pedrosoi , F. monophora and F. nubica , with fungicidal activity for F. pedrosoi and F. monophora . MMV688415 presented synergism with itraconazole only for F. pedrosoi , with fungicidal activity. The synergic compounds had high selectivity index values when combined with itraconazole. MAIN CONCLUSIONS These compounds in combination, particularly SQ109, are promising candidates to treat Fonsecaea spp. and E. dermatitidis infections, which account for most cases of chromoblastomycosis and phaeohyphomycosis.

Chromoblastomycosis successfully treated with the combination of itraconazole and 5-flucytosine

“…In our patient, combined therapy with ITZ and 5-FC was used with good clinical response, although the most common antifungal association is ITZ and terbinafine. reported an interesting case of severe chromoblastomycosis mistreated over 20 years, which was successfully treated with ITZ and 5-FC association [22,23]. Flucytosine is a pyrimidine derivative and antimetabolite agent, with its main activity in inhibiting the synthesis of nucleic acids in fungal cells.…”