Laboratório de Microbiologia Médica, Universidade Federal de São João del-Rei (UFSJ)-Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil.
Laboratório de Síntese Orgânica e Nanoestruturas, Universidade Federal de São João del-Rei (UFSJ)-Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil.
J Antibiot (Tokyo). 2018 Aug;71(8):702-712. doi: 10.1038/s41429-018-0048-9. Epub 2018 Apr 19.
Vulvovaginal candidiasis (VVC) affects millions of women around the world every year. Candida albicans is the most frequently isolated pathogen in women and its rapid ability to develop resistance to first and second line therapies has boosted the search for new and effective antifungal agents. In this study, we show the in vitro anti-Candida activity of fifteen synthetic chalcone analogs and their antifungal potential in an in vivo model of VVC. Chalcone 12 showed potent antifungal effects, being able to inhibit the growth of Candida spp. at a concentration of 15.6 µg mL. In addition, mechanism of action studies have indicated the ergosterol fungal membrane as the target of this compound. Despite a considerable antifungal activity, the chalcone 12 showed high cytotoxicity in kidney cells lineages. Moreover, this compound was able to reduce Candida-associated virulence, impairing yeast-hyphal transition in C. albicans. An in vivo model of VVC showed that chalcone 12 significantly reduces the fungal load. Taken together, these findings showed that the chalcone 12 is a potent anti-Candida agent in vitro beyond of contribute to improve the fungal infection in a model of CVV. However, it showed low selectivity and high toxicity, suggesting molecular modifications to minimize these proprieties.
外阴阴道念珠菌病（VVC）每年影响全球数百万妇女。白色念珠菌是女性最常分离的病原体，其对一线和二线治疗药物迅速产生耐药性，这促使人们寻找新的有效抗真菌药物。在这项研究中，我们展示了十五种合成查尔酮类似物的体外抗念珠菌活性及其在 VVC 体内模型中的抗真菌潜力。查尔酮 12 表现出很强的抗真菌作用，能够在 15.6μg/ml 的浓度下抑制念珠菌属的生长。此外，作用机制研究表明，该化合物的作用靶点是真菌麦角固醇膜。尽管具有相当大的抗真菌活性，但查尔酮 12 在肾细胞系中显示出高细胞毒性。此外，该化合物能够降低念珠菌相关的毒力，损害白色念珠菌中的酵母-菌丝过渡。VVC 的体内模型表明，查尔酮 12 可显著降低真菌负荷。总之，这些发现表明，查尔酮 12 是一种有效的体外抗念珠菌剂，除了有助于改善 CVV 中的真菌感染外。然而，它表现出低选择性和高毒性，表明需要进行分子修饰以最小化这些特性。
