Discovery of a Novel Class of Orally Active Antifungal β-1,3-D-Glucan Synthase Inhibitors
Discovery of a Novel Class of Orally Active Antifungal β-1,3-D-Glucan Synthase Inhibitors
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DOI：
10.1128/aac.00432-11
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Black, Todd A.
中科院分区：
文献类型：
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作者：
Walker, Scott S.;Xu, Yiming;Black, Todd A.
棘球蛋白是一类以β-1，3-葡聚糖合成酶(GS)为靶点的半合成天然产物。它们被证明的临床有效性，加上最小的安全性问题，使棘球菌素成为在各种患者群体中管理真菌感染的重要资产。然而，棘球蛋白只能通过非肠道给药。抗真菌生物活性筛选结合作用机制研究确定了一类以GS为靶标的哌嗪基哒嗪酮类化合物。这些化合物在体外表现出与棘球蛋白类似的活性，在某些情况下甚至更好。这些化合物在体外对GS有抑制作用，酶抑制作用与体外抗真菌活性有很强的相关性。此外，与棘球菌素一样，这些化合物导致酵母细胞质内容物的泄漏，并在霉菌中产生具有GS抑制剂特征的形态反应。对哌嗪基哒嗪酮类敏感性降低的酿酒酵母自发突变株在FKS1中发生了替换。这些替换的位置与那些赋予棘球菌素耐药性的位置不同；同样，对棘球菌素耐药的分离株仍然对测试化合物敏感。最后，我们给出了一个哌嗪基哒嗪酮类化合物的有效性和药代动力学数据，该化合物在光滑念珠菌感染的小鼠模型中证明了有效性。
The echinocandins are a class of semisynthetic natural products that target beta-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.