Borba-Santos Luana Pereira, Rollin-Pinheiro Rodrigo, da Silva Fontes Yasmin, Dos Santos Giulia Maria Pires, de Sousa Araújo Glauber Ribeiro, Rodrigues Anderson Messias, Guimarães Allan J, de Souza Wanderley, Frases Susana, Ferreira-Pereira Antonio, Barreto-Bergter Eliana, Rozental Sonia
Laboratório de Biologia Celular de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
Laboratório de Química Biológica de Microrganismos, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
J Fungi (Basel). 2022 Sep 25;8(10):1004. doi: 10.3390/jof8101004.
The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching for new drug candidates. In this study, we screened the Pandemic Response Box library (Medicines for Malaria Venture) of 400 diverse molecules against the pathogenic species. The initial screen identified twenty-four candidates that inhibited the growth of by more than 80%. Some of these compounds are known to display antifungal activity, including olorofim (MMV1782354), a new antifungal drug. Olorofim inhibited and killed the yeasts of , , and at concentrations lower than itraconazole, and it also showed antibiofilm activity. According to the results obtained by fluorimetry, electron microscopy, and particle characterization analyses, we observed that olorofim induced profound alterations on the cell surface and cell cycle arrest in yeasts. We also verified that these morphophysiological alterations impaired their ability to adhere to keratinocytes in vitro. Our results indicate that olorofim is a promising new antifungal against sporotrichosis agents.
真菌感染的患病率和严重程度增加以及对现有抗真菌药物的耐药性凸显了对新型治疗方法的迫切需求以及寻找新靶点的必要性。对包含数百种化合物的文库进行高内涵筛选是寻找新候选药物的有力策略。在本研究中，我们针对致病菌种筛选了由400种不同分子组成的大流行应对药物库（疟疾药物风险投资公司）。初步筛选确定了24种抑制[具体菌种]生长超过80%的候选物。其中一些化合物已知具有抗真菌活性，包括新型抗真菌药物奥洛菲姆（MMV1782354）。奥洛菲姆在低于伊曲康唑的浓度下就能抑制并杀死[具体菌种]、[具体菌种]和[具体菌种]的酵母，并且还表现出抗生物膜活性。根据荧光测定、电子显微镜和颗粒表征分析获得的结果，我们观察到奥洛菲姆在[具体菌种]酵母中诱导了细胞表面的深刻改变和细胞周期停滞。我们还证实，这些形态生理改变损害了它们在体外黏附角质形成细胞的能力。我们的结果表明，奥洛菲姆是一种有前景的抗孢子丝菌病新型抗真菌药物。
