Goffena Joy, Toenjes Kurt A, Butler David K
Department of Biological and Physical Sciences, Montana State University - Billings, Billings, Montana, 59101, USA.
Yeast. 2018 Mar;35(3):291-298. doi: 10.1002/yea.3287. Epub 2017 Nov 29.
The opportunistic fungal pathogen of humans Candida albicans is able to grow in different morphological forms such as round or oval yeasts and filamentous hyphae and pseudohyphae. Morphogenesis, the ability to switch between the yeast and filamentous growth forms, is important for adapting to new microenvironments in the human host and for pathogenesis. The molecular pathways governing morphogenesis are complex and incompletely understood. Previously, we identified several small organic molecules that specifically inhibit the initiation of hyphal growth in C. albicans without affecting cell viability or budded growth. One molecule from that screen is known to induce apoptosis in mammalian cells. In this study, we have screened additional inducers of mammalian apoptosis and identified BH3I-1, as well as several structural derivatives of BH3I-1, that act as specific inhibitors of morphogenesis under a variety of environmental conditions. Chemical epistasis experiments suggest that BH3I-1 acts downstream of the hypha-specific gene regulators Rfg1, Nrg1 and Ume6.
人类机会性真菌病原体白色念珠菌能够以不同的形态形式生长，如圆形或椭圆形酵母以及丝状菌丝和假菌丝。形态发生，即酵母和丝状生长形式之间转换的能力，对于适应人类宿主中的新微环境和发病机制很重要。控制形态发生的分子途径很复杂且尚未完全了解。此前，我们鉴定了几种小分子有机化合物，它们能特异性抑制白色念珠菌中菌丝生长的起始，而不影响细胞活力或出芽生长。已知该筛选中的一种分子可诱导哺乳动物细胞凋亡。在本研究中，我们筛选了更多的哺乳动物细胞凋亡诱导剂，并鉴定出BH3I-1以及BH3I-1的几种结构衍生物，它们在多种环境条件下作为形态发生的特异性抑制剂。化学上位性实验表明，BH3I-1在菌丝特异性基因调节因子Rfg1、Nrg1和Ume6的下游起作用。
