Highly Stable, Amide-Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus.
Highly Stable, Amide-Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus.
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DOI：
10.1002/anie.201602974
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发表时间：
2016-07-25
期刊：
影响因子：
--
通讯作者：
Blackwell HE
中科院分区：
文献类型：
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作者：
Tal-Gan Y;Ivancic M;Cornilescu G;Yang T;Blackwell HE
阻断群体感应（quorum sensing，QS）途径作为抑制细菌病原体毒力的方法已经引起了相当大的兴趣。为了实现这一目标，我们最近开发了一种天然自诱导肽（AIP-III）信号的类似物，可以抑制AgrC型QS受体并减弱金黄色葡萄球菌的毒力表型。然而，这些化合物的应用是有限的，因为它们含有水解不稳定的硫酯键并且仅具有低的水溶解度。在此，我们报道了酰胺连接的AIP类似物，其相对于我们先前的类似物具有大大增强的水解稳定性和溶解性，同时保持作为S.金黄色。这些化合物代表了QS研究的强大新工具。报道了金黄色葡萄球菌中肽类群体感应抑制剂的新内酰胺类似物，其具有显著增强的物理性质，同时保持其强的生物活性。结构分析表明，它们采用类似于其硫酯前体的构象，并证实了它们在基于细胞的AgRC型受体调节测定中的活性。
Blocking quorum sensing (QS) pathways has attracted considerable interest as an approach to suppress virulence in bacterial pathogens. Toward this goal, we recently developed analogues of a native autoinducing peptide (AIP-III) signal that can inhibit AgrC-type QS receptors and attenuate virulence phenotypes in Staphylococcus aureus. Application of these compounds is limited, however, as they contain hydrolytically unstable thioester linkages and have only low aqueous solubilities. Herein, we report amide-linked AIP analogues with greatly enhanced hydrolytic stabilities and solubilities relative to our prior analogues, whilst maintaining strong potencies as AgrC receptor inhibitors in S. aureus. These compounds represent powerful new tools for the study of QS. New lactam analogues of peptidic quorum sensing inhibitors in Staphylococcus aureus are reported with significantly enhanced physical prosperities, whilst maintaining their strong biological activities. Structural analyses reveal that they adopt conformations similar to their thioester precursors, and corroborate their activities in cell-based assays for AgrC-type receptor modulation.