A screening of the MMV Pathogen Box® reveals new potential antifungal drugs against the etiologic agents of chromoblastomycosis
A screening of the MMV Pathogen Box® reveals new potential antifungal drugs against the etiologic agents of chromoblastomycosis
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DOI：
10.1371/journal.pone.0229630
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发表时间：
2020-05-13
期刊：
影响因子：
3.7
通讯作者：
Almeida-Paes, Rodrigo
中科院分区：
文献类型：
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作者：
Coelho, Rowena Alves;Joffe, Luna Sobrino;Almeida-Paes, Rodrigo
成色菌病（CBM）是一种由多种黑色真菌外伤性植入引起的慢性皮下真菌病。由于一些病例的难治性和CBM的常见复发，更有效和更短时间的治疗是强制性的。本研究的目的是鉴定病原菌箱（病原菌箱）化合物收集中对不同CBM药物具有体外抗真菌活性的化合物。还评估了这些化合物与目前用于治疗CBM的药物的协同作用。根据EUCAST方案，在1 μ M处对该收集物中存在的药物进行初步筛选，使用Fonsecaea pedrosoi临床菌株。在0.039 ~ 10 μ m的浓度范围内，对其他7种病原菌（腐斑Cladophialophora carrionii、疣斑phalophora verrucosa、jeanselexophiala jeanselmei、皮炎Exophiala monophora、nubica Fonsecaea和Rhinocladiella similis）进行了抑菌活性测定，并采用棋盘法分析了这些化合物与伊曲康唑和特比萘芬的协同作用。8种化合物抑制了60%以上的油松菌生长，它们分别是：二苯醚康唑、双醇、碘喹啉、氮氧虫酯、MMV688179、MMV021013、三氟虫酯和金糠蛋白。碘喹诺的MIC值最低（1.25 ~ 2.5 μ M）， MMV688179的MIC值高于所有化合物（5 ~ 10 μ M）。当金糠蛋白与伊曲康唑联合使用时，对腐肉杆菌具有协同作用（FICI = 0.37）。毒性分析表明，MMV021013对真菌具有较高的选择性指数（SI >= 10）。综上所述，金糠蛋白、碘喹啉和MMV021013被认为是有希望在CBM感染模型中进行测试的化合物。
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 (R) 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 mu M 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 mu M. 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 mu M) and MMV688179 showed MICs that were higher than all compounds tested (5 - >10 mu M). 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.