Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
Department of Dermatology, Changhai Hospital, Naval Medical University, Shanghai, 200438, China.
Appl Microbiol Biotechnol. 2024 Dec;108(1):96. doi: 10.1007/s00253-023-12996-1. Epub 2024 Jan 11.
Fungal infections are increasing rapidly, and antifungal agents used in clinics are limited. Therefore, novel antifungal agents with high efficiency are urgently required. In this study, we investigated the antifungal activity of thonningianin A (THA), a natural compound that is widely found in plants. We first determined the activity of THA against Candida albicans, one of the most common fungal pathogens, and found that THA showed antifungal activity against all C. albicans tested, including several fluconazole-resistant isolates. THA also inhibits the growth of non-Candida albicans species. In addition, THA displayed antibiofilm activity and could not only inhibit biofilm formation but also destroy mature biofilms. The in vivo antifungal efficacy of THA was confirmed in a Galleria mellonella infection model. Further studies revealed that THA could enhance intracellular reactive oxygen species (ROS) production and regulate the transcription of several redox-related genes. Specifically, caspase activity and expression of CaMCA1, a caspase-encoding gene in C. albicans, were remarkably increased upon THA treatment. Consistent with this, in the presence of THA, the Camca1 null mutant displayed higher survival rates and reduced caspase activity compared to the wild-type or CaMCA1-reintroduced strains, indicating an important role of CaMCA1 in the antifungal activity of THA. Taken together, our results indicate that THA possesses excellent antifungal activity and may be a promising novel antifungal candidate. KEY POINTS: • THA exhibits activity against Candida species, including fluconazole-resistant isolates • THA inhibits biofilm formation and destroys mature biofilm • Elevated ROS production and CaMCA1-mediated caspase activity are involved in the antifungal mechanisms of THA.
真菌感染迅速增加，临床使用的抗真菌药物有限。因此，迫切需要高效的新型抗真菌药物。在这项研究中，我们研究了广泛存在于植物中的天然化合物托宁宁 A（THA）的抗真菌活性。我们首先确定了 THA 对白色念珠菌（一种最常见的真菌病原体）的活性，发现 THA 对所有测试的白色念珠菌均显示出抗真菌活性，包括几种氟康唑耐药株。THA 还抑制非白色念珠菌物种的生长。此外，THA 显示出抗生物膜活性，不仅可以抑制生物膜形成，还可以破坏成熟的生物膜。THA 在大蜡螟感染模型中证实了体内抗真菌功效。进一步的研究表明，THA 可以增强细胞内活性氧（ROS）的产生并调节几个氧化还原相关基因的转录。具体而言，THA 处理后，白色念珠菌中的 Caspase 编码基因 CaMCA1 的 Caspase 活性和表达显著增加。与此一致，在 THA 存在的情况下，与野生型或 CaMCA1 重新引入的菌株相比，Camca1 缺失突变体的存活率更高，Caspase 活性降低，表明 CaMCA1 在 THA 的抗真菌活性中起重要作用。总之，我们的结果表明 THA 具有出色的抗真菌活性，可能是一种有前途的新型抗真菌候选药物。要点：• THA 对包括氟康唑耐药株在内的念珠菌属具有活性• THA 抑制生物膜形成并破坏成熟生物膜• 升高的 ROS 产生和 CaMCA1 介导的 Caspase 活性参与了 THA 的抗真菌机制。
