Triazine-Based Small Molecules: A Potential New Class of Compounds in the Antifungal Toolbox.
Triazine-Based Small Molecules: A Potential New Class of Compounds in the Antifungal Toolbox.
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DOI：
10.3390/pathogens12010126
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发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
Rauceo JM
中科院分区：
文献类型：
--
作者：
Conrad KA;Kim H;Qasim M;Djehal A;Hernday AD;Désaubry L;Rauceo JM
念珠菌引起的侵袭性真菌感染仍然是世界范围内一个重大的公共卫生问题。耐药感染的日益流行和有限的抗真菌药物库强调需要新的干预措施。在此，我们筛选了几种对哺乳动物疾病具有药理活性的化合物的抗真菌活性。我们发现合成的以三嗪为基础的化合物melanogenin (Mel) 56对白色念珠菌实验室和临床菌株具有杀真菌作用，最低抑菌浓度为8-16µg/mL。此外，Mel56对几种非白色念珠菌和非致病性酿酒酵母具有普遍的抗真菌活性。令人惊讶的是，Mel56在亚致死浓度下抑制了酵母到菌丝的转变，揭示了三嗪类化合物在真菌中的新作用。在人类癌细胞系中，Mel56靶向线粒体内整体膜禁止蛋白PHB1和PHB2。然而，Mel56处理并没有影响白色念珠菌的线粒体活性，并且与野生型亲本菌株相比，禁止单、双、三重纯合突变菌株的抗真菌活性相似。这些结果表明Mel56在白色念珠菌中具有一种新的作用机制。因此，Mel56是一个有前景的抗真菌候选物，值得进一步分析。
Invasive fungal infections caused by Candida species remain a significant public health problem worldwide. The increasing prevalence of drug-resistant infections and a limited arsenal of antifungal drugs underscore the need for novel interventions. Here, we screened several classes of pharmacologically active compounds against mammalian diseases for antifungal activity. We found that the synthetic triazine-based compound melanogenin (Mel) 56 is fungicidal in Candida albicans laboratory and clinical strains with minimal inhibitory concentrations of 8–16 µg/mL. Furthermore, Mel56 has general antifungal activity in several non-albicans Candida species and the non-pathogenic yeast Saccharomyces cerevisiae. Surprisingly, Mel56 inhibited the yeast-to-hyphae transition at sublethal concentrations, revealing a new role for triazine-based compounds in fungi. In human cancer cell lines, Mel56 targets the inner mitochondrial integral membrane prohibitin proteins, PHB1 and PHB2. However, Mel56 treatment did not impact C. albicans mitochondrial activity, and antifungal activity was similar in prohibitin single, double, and triple homozygous mutant strains compared to the wild-type parental strain. These results suggests that Mel56 has a novel mechanism-of-action in C. albicans. Therefore, Mel56 is a promising antifungal candidate warranting further analyses.
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