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Chromoblastomycosis (CBM) is a neglected human implantation mycosis caused by several dematiaceous fungal species. Currently available therapy is usually associated with physical methods, especially surgery, and with high refractoriness. Therefore, drug discovery for CBM is essential. Drug repositioning is a strategy used to facilitate the discovery of new treatments for several diseases. The aim of this study was to discover substances with antifungal activity against CBM agents from a collection of drugs previously approved for use in human diseases. A screening was performed with the NIH Clinical Collection against Fonsecaea pedrosoi. Ten substances, with clinical applicability in CBM, inhibited fungal growth by at least 60%. The minimum inhibitory concentration (MIC) of these substances was determined against other CBM agents, and the benzimidazoles albendazole, mebendazole and thiabendazole presented the lowest MIC values. The selectivity index, based on MIC and cytotoxicity of these substances, revealed albendazole to be more selective. To investigate a possible synergism of this benzimidazole with itraconazole and terbinafine, the chequerboard method was used. All interactions were classified as indifferent. Our current results suggest that benzimidazoles have repositioning potential against CBM agents. Albendazole seems to be the most promising, since it presented the highest selectivity against all dematiaceous fungi tested. [ABSTRACT FROM AUTHOR]

Several human pathogenic fungi produce melanin. One of its properties during parasitism is the protection against antifungal drugs. This occurs with the agents of chromoblastomycosis, in which DHN-melanin reduces antifungal susceptibility to terbinafine and itraconazole. Since these agents are resistant to some antifungal drugs, we investigated the role of DHN-melanin on the Fonsecaea susceptibility to amphotericin B, micafungin, fluconazole, and flucytosine, drugs that usually present high minimal inhibitory concentrations (MIC) to this genus. Seven strains from three Fonsecaea human pathogenic species were treated with tricyclazole, a DHN-melanin inhibitor, and the MIC of the treated and untreated cells were compared. A survival assay was performed to confirm the alterations in the susceptibility of strains with reduced melanization, and the chitin levels of the strains were estimated by fluorescence. Tricyclazole did not affect fluconazole and flucytosine MIC, while melanin inhibition increased susceptibility to amphotericin B. Surprisingly, DHN-melanin inhibition decreased the susceptibility to micafungin. Survival assays confirmed this result on five strains. Cell wall chitin levels of the strains were not associated with the decrease in micafungin susceptibility. The results show that DHN-melanin does not have a role in the intrinsic resistance of Fonseacaea spp. to amphotericin B, fluconazole, and flucytosine, and its inhibition may promote micafungin resistance. [ABSTRACT FROM AUTHOR]

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis caused by traumatic implantation of many species of black fungi. Due to the refractoriness of some cases and common recurrence of CBM, a more effective and less time-consuming treatment is mandatory. The aim of this study was to identify compounds with in vitro antifungal activity in the Pathogen Box® compound collection against different CBM agents. Synergism of these compounds with drugs currently used to treat CBM was also assessed. An initial screening of the drugs present in this collection at 1 μM was performed with a Fonsecaea pedrosoi clinical strain according to the EUCAST protocol. The compounds with activity against this fungus were also tested against other seven etiologic agents of CBM (Cladophialophora carrionii, Phialophora verrucosa, Exophiala jeanselmei, Exophiala dermatitidis, Fonsecaea monophora, Fonsecaea nubica, and Rhinocladiella similis) at concentrations ranging from 0.039 to 10 μM. The analysis of potential synergism of these compounds with itraconazole and terbinafine was performed by the checkerboard method. Eight compounds inhibited more than 60% of the F. pedrosoi growth: difenoconazole, bitertanol, iodoquinol, azoxystrobin, MMV688179, MMV021013, trifloxystrobin, and auranofin. Iodoquinol produced the lowest MIC values (1.25–2.5 μM) and MMV688179 showed MICs that were higher than all compounds tested (5 - >10 μM). When auranofin and itraconazole were tested in combination, a synergistic interaction (FICI = 0.37) was observed against the C. carrionii isolate. Toxicity analysis revealed that MMV021013 showed high selectivity indices (SI ≥ 10) against the fungi tested. In summary, auranofin, iodoquinol, and MMV021013 were identified as promising compounds to be tested in CBM models of infection. [ABSTRACT FROM AUTHOR]