Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis
Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis
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DOI：
10.1073/pnas.1305982110
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发表时间：
2013-08-13
影响因子：
11.1
通讯作者：
Kaufman, Paul D.
中科院分区：
文献类型：
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作者：
Fazly, Ahmed;Jain, Charu;Kaufman, Paul D.
白色念珠菌等病原真菌的感染首先粘附在宿主细胞或植入的医疗设备上，然后形成生物膜。通过小分子的高通量表型筛选，我们鉴定了抑制白色念珠菌与聚苯乙烯粘附的化合物。我们的主要候选化合物还抑制白色念珠菌与培养的人上皮细胞的结合、酵母到菌丝的形态转变、菌丝特异性 HWP1 启动子的诱导、有机硅弹性体上生物膜的形成、线虫感染模型中的发病机制以及改变小鼠粘膜感染测定中的真菌形态。我们将这种化合物称为非司他汀，是因为它对丝状形成有很强的抑制作用，并且我们使用化学遗传学实验来证明它在多种信号通路的下游发挥作用。这些研究表明，针对真菌粘附的高通量功能测定可以为研究真菌发病机制的多个方面提供化学探针。
Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.