Highly Potent Inhibitors of Quorum Sensing in Staphylococcus aureus Revealed Through a Systematic Synthetic Study of the Group-III Autoinducing Peptide
Highly Potent Inhibitors of Quorum Sensing in Staphylococcus aureus Revealed Through a Systematic Synthetic Study of the Group-III Autoinducing Peptide
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DOI：
10.1021/ja3112115
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发表时间：
2013-05-29
影响因子：
15
通讯作者：
Blackwell, Helen E.
中科院分区：
文献类型：
--
作者：
Tal-Gan, Yftah;Stacy, Danielle M.;Blackwell, Helen E.
阻断细菌群体感应(QS)的方法作为潜在的抗感染治疗方法已引起人们的极大关注。金黄色葡萄球菌是一种主要的人类病原体，它利用自身诱导肽(AIP)信号来调节QS，从而调节毒力。根据AIP信号和同源胞外受体AGRC，金黄色葡萄球菌菌株分为四组(I-IV)。每组都与特定的疾病相关联，金黄色葡萄球菌组的Ill菌株是中毒性休克综合征的罪魁祸首，到目前为止在其他感染中被低估了。一组有限的非天然AIP类似物已被证明可以抑制AGRC受体；这些化合物是研究金黄色葡萄球菌QS途径的有前途的工具。我们寻求扩展这套化学探针，并在此报告第一次设计、合成和生物测试AIP-III模拟物。在报告菌株中发现了一组非天然多肽，它们能抑制报告菌株的所有四种AGRC受体(I-IV)，IC50值为皮摩尔。这些类似物在皮摩尔浓度下也能抑制野生型金黄色葡萄球菌I-IV菌株的溶血--这是一种受qs控制的毒力特性。此外，在野生型金黄色葡萄球菌Ill株中，四种先导AGRC抑制剂在纳摩尔浓度下能够抑制中毒休克综合征毒素-1的产生(也受qs控制)超过80%。据我们所知，这些多肽代表了已知的金黄色葡萄球菌中最有效的QS合成抑制剂，并构成了新的、容易获得的化学工具，用于研究这种致命病原体的AGRC系统和毒力。
Methods to intercept bacterial quorum sensing (QS) have attracted significant attention as potential anti-infective therapies. Staphylococcus aureus is a major human pathogen that utilizes autoinducing peptide (AIP) signals to mediate QS and thereby regulate virulence. S. aureus strains are categorized into four groups (I-IV) according to their AIP signal and cognate extracellular receptor, AgrC. Each group is associated with a certain disease profile, and S. aureus group Ill strains are responsible for toxic shock syndrome and have been underestimated in other infections to date. A limited set of non-native AIP analogs have been shown to inhibit AgrC receptors; such compounds represent promising tools to study QS pathways in S. aureus. We seek to expand this set of chemical probes and report herein the first design, synthesis, and biological testing of AIP-III mimetics. A set of non-native peptides was identified that can inhibit all four of the AgrC receptors (I-IV) with picomolar IC50 values in reporter strains These analogs also blocked hemolysis by wild type S. aureus group I-IV strains-a virulence trait under the control of QS-at picomolar concentrations Moreover, four of the lead AgrC inhibitors were capable of attenuating the production of toxic shock syndrome toxin -1 (also under the control of QS) by over 80% at nanomolar concentrations in a wild type S. aureus group Ill strain. These peptides represent, to our knowledge, the most potent synthetic inhibitors of QS in S. aureus known, and constitute new and readily accessible chemical tools for the study of the AgrC system and virulence in this deadly pathogen.