Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
Faculty of Pharmacy and Biochemistry, University of Zagreb, Schrottova 39, 10000 Zagreb, Croatia.
Molecules. 2021 Jun 8;26(12):3504. doi: 10.3390/molecules26123504.
The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50-62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.
可用于治疗真菌感染的药物数量有限，这使得真菌病原体的控制成为一个问题，尤其是因为真菌耐药性事件的数量在不断增加。鉴于新抗真菌治疗方案的成本高且开发速度慢，重新利用已有的化合物是提出的策略之一。本研究的目的是对我们之前在计算机药物再利用研究中已经确定的先导化合物进行体外实验测试，该研究是在已知的 Drugbank 数据库上使用包括机器学习和分子对接在内的七步程序进行的。本研究确定了西拉美辛是一种新型抗真菌药物。通过对几种酵母和一种霉菌进行体外测试，证实了这一新的适应症。结果表明，[微生物名称]对西拉美辛敏感，MIC 浓度为 12.5µg/mL，而其他候选药物则没有抗真菌活性。西拉美辛还能有效抑制体外生物膜的形成，在经过 24 小时治疗后，其 MBEC 范围为 50-62.5µg/mL，已经形成的生物膜减少。西拉美辛在体外还参与了麦角固醇生物合成的调节，这表明它是其抗真菌活性的潜在靶点。这意味着西拉美辛可能被重新利用，尤其是因为已经有关于其非毒性的已发表数据。根据我们的体外结果，我们对西拉美辛和结构上类似于西拉美辛的化合物进行了额外的深入计算机分析，为进一步的临床前和临床研究提供了扩展的先导化合物集，这是明确定义分子靶点和阐明其体内有效性所必需的。
