Abstract
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.
Highlights
Chromoblastomycosis (CBM) is a subcutaneous neglected mycosis [1]
Black fungi from the genera Fonsecaea, Cladophialophora, Rhinocladiella, Phialophora, Exophiala, among others, can cause CBM. Since this mycosis is not of compulsory notification in most countries where it occurs, its distribution is based on case reports and case series, with most of them occurring in Latin America, Africa, and Asia
In South America, most of the cases of CBM have been described in Brazil, in Africa most cases come from Madagascar, and China is the leading Asian country on number of cases [2]
Summary
Chromoblastomycosis (CBM) is a subcutaneous neglected mycosis [1] It is caused by the implantation of one of its etiological agents through a trauma to the skin. Black fungi from the genera Fonsecaea, Cladophialophora, Rhinocladiella, Phialophora, Exophiala, among others, can cause CBM. Since this mycosis is not of compulsory notification in most countries where it occurs, its distribution is based on case reports and case series, with most of them occurring in Latin America, Africa, and Asia. In South America, most of the cases of CBM have been described in Brazil, in Africa most cases come from Madagascar, and China is the leading Asian country on number of cases [2]. F. pedrosoi predominates in humid regions of most countries where CBM is endemic, including Madagascar and China. The frequency of infections by species belonging to other genera of black fungi varies among different geographic regions [2]
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