Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P.
Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P.
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DOI：
10.1021/acs.jnatprod.5b01091
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发表时间：
2016-04-22
影响因子：
5.1
通讯作者：
Duerfeldt AS
中科院分区：
文献类型：
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作者：
Lavey NP;Coker JA;Ruben EA;Duerfeldt AS
酪蛋白分解蛋白酶P（Caseinolytic protease P，ClpP）在细菌体内平衡中起重要作用。因此，这种酶的抑制和激活都导致杀菌活性，使ClpP成为抗菌药物开发的有希望的靶标。在此，我们报告了~450种结构不同的真菌和细菌次级代谢产物的荧光筛选结果。Sclerotiamide（1）是一种与paraherquamide相关的吲哚啉酮，被鉴定为ClpP的第一个非肽基天然产物激活剂。结构-活性关系所产生的初步筛选，初步的生化评价1，和开发这种化学型开发新的ClpP激活剂的理由。
Caseinolytic protease P (ClpP) maintains essential roles in bacterial homeostasis. As such, both the inhibition and activation of this enzyme result in bactericidal activity, making ClpP a promising target for antibacterial drug development. Herein, we report the results of a fluorescence-based screen of ~450 structurally diverse fungal and bacterial secondary metabolites. Sclerotiamide (1), a paraherquamide-related indolinone, was identified as the first non-peptide-based natural product activator of ClpP. Structure-activity relationships arising from the initial screen, preliminary biochemical evaluation of 1, and rationale for the exploitation of this chemotype to develop novel ClpP activators are presented.