A screening of the MMV Pathogen Box® reveals new potential antifungal drugs against the etiologic agents of chromoblastomycosis

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.

Identification of two potential inhibitors of Sporothrix brasiliensis and Sporothrix schenckii in the Pathogen Box collection

“…of Candida species and chromoblastomycosis agents [16,17]. The IC 50 for planktonic cells of Candida spp.…”

“…observed with 1.25 μM iodoquinol [16,17]. Therefore, a comprehensive study including a panel of diverse fungi would be of interest to elucidate whether iodoquinol has a broad spectrum of antifungal activity.…”

“…The Pathogen Box library, developed by the Medicines for Malaria Venture organization (MMV), contains 400 compounds with repurposing potential and also new molecules ( https://www.mmv.org/mmv-open/pathogen-box ), selected on the basis of their promising activity against pathogens associated with neglected tropical diseases [ 13 ]. In an effort to identify new molecules with antifungal activity, the Pathogen Box library was previously screened for its antifungal activity against Candida species, Cryptococcus species, and chromoblastomycosis agents [ 14 – 17 ]. Thus, the purpose of this study was to screen this collection in search of compounds with potential anti- S .…”

Cinnamyl Schiff bases: synthesis, cytotoxic effects and antifungal activity of clinical interest

“…The higher the SI of a substance is, the safer it is. Thus, we considered the compounds that exhibited SI values equal to or higher than 10 to be good lead compounds for further studies of in vivo antifungal efficacy (Orme 2001;Soares et al 2014;Coelho et al 2020).…”

“…Schiff bases correspond to an interesting class of organic compounds, mainly due to their broad range of biological properties. Several reports in the literature indicate that Schiff base derivatives are promising lead compounds for new antibacterials, antileishmanials, antiplasmodials, trypanocidals and antifungals (Razakantoanina et al 2000;Al-Kahraman et al 2010;da Silva et al 2011;Magalhães et al 2013;Ceruso et al 2015;Gasparotto et al 2015;Almeida et al 2018). On the other hand, cinnamaldehyde also exhibits several biological properties, particularly with regard to growth inhibition of fungi and bacteria (Li et al 2015;Doyle et al 2019).…”