Simplified Autoinducing Peptide Mimetics with Single-Nanomolar Activity Against the Staphylococcus aureus AgrC Quorum Sensing Receptor
Simplified Autoinducing Peptide Mimetics with Single-Nanomolar Activity Against the Staphylococcus aureus AgrC Quorum Sensing Receptor
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DOI：
10.1021/acsinfecdis.9b00002
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发表时间：
2019-04-01
影响因子：
5.3
通讯作者：
Blackwell, Helen E.
中科院分区：
文献类型：
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作者：
Vasquez, Joseph K.;Blackwell, Helen E.
金黄色葡萄球菌是世界范围内医院获得性感染的主要原因，社区获得性感染的病例正变得越来越普遍。金黄色葡萄球菌多种毒力因子的产生受辅助基因调控（agr）群体感应（QS）系统的控制。金黄色葡萄球菌在高细胞密度下通过分泌肽信息素或自诱导肽（AIP）来上调agr，这可以通过其同源跨膜受体AgrC检测到。AgrC的胞外AIP结合位点是抑制agr系统的一个有吸引力的靶点，因此，在金黄色葡萄球菌中，qs控制了毒力。据报道，非天然肽和最近的肽拟物可以抑制AgrC受体，这是研究QS在金黄色葡萄球菌感染中的作用的有用化学工具。我们寻求在肽样支架之外扩展，以生成相对于这些化合物具有更高稳定性、溶解度和合成可及性的AgrC调节剂，同时保持其高效力。为了实现这一目标，我们在此报道了最近报道的简化AIP模拟物和AgrC拮抗剂n7OFF的结构活性关系的研究，并发现了一种新的AIP模拟物b3c3，它在所有四个金黄色葡萄球菌agr特异性组中具有低至亚纳摩尔的抑制活性。核磁共振结构研究显示b3c3的疏水性和亲水性可能是AgrC拮抗的关键，这与先前对肽衍生抑制剂的研究一致。b3c3是开发小分子AgrC拮抗剂的重要过渡化合物。
Staphylococcus aureus is a leading cause of hospital-acquired infections worldwide, and cases of community-acquired infections are becoming more prevalent. The production of numerous virulence factors in S. aureus is under the control of the accessory gene regulator (agr) quorum sensing (QS) system. S. aureus upregulates agr at high cell density by secreting a peptide pheromone, or autoinducing peptide (AIP), which is detected by its cognate transmembrane receptor, AgrC. The extracellular AIP binding site of AgrC represents an attractive target for inhibition of the agr system and, thereby, QS-controlled virulence in S. aureus. Nonnative peptides and, more recently, peptidomimetics have been reported to inhibit the AgrC receptor and represent useful chemical tools to study the role of QS in S. aureus infections. We seek to expand beyond peptide-like scaffolds to generate AgrC modulators with enhanced stability, solubility, and synthetic accessibility relative to these compounds, while maintaining their high potencies. Toward this goal, we report herein a study of the structure activity relationships responsible for the activity of a recently reported simplified AIP mimetic and AgrC antagonist, n7OFF, and the discovery of a new AIP mimetic, Bnc3, which has low- to sub-nanomolar inhibitory activity in all four S. aureus agr specificity groups. NMR structural studies of Bnc3 revealed hydrophobic and hydrophilic faces that are likely critical for AgrC antagonism, in agreement with prior studies of peptide-derived inhibitors. Bnc3 represents an important transition compound toward the development of small-molecule AgrC antagonists.