Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, Wisconsin 53706, United States.
Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, Colorado 80045, United States.
J Am Chem Soc. 2024 Jun 12;146(23):15941-15954. doi: 10.1021/jacs.4c02694. Epub 2024 Jun 4.
The pathogen uses a chemical signaling process, i.e., quorum sensing (QS), to form robust biofilms and cause human infection. Many questions remain about QS in , as it uses this intercellular communication pathway to both negatively and positively regulate virulence traits. Herein, we report synthetic multigroup agonists and antagonists of the accessory gene regulator () QS system capable of potent superactivation and complete inhibition, respectively. These macrocyclic peptides maintain full efficacy across the three major specificity groups, and their activity can be "mode-switched" from agonist to antagonist via subtle residue-specific structural changes. We describe the design and synthesis of these non-native peptides and demonstrate that they can appreciably decrease biofilm formation on abiotic surfaces, underscoring the potential for agonism as a route to block virulence. Additionally, we show that both the agonists and antagonists are active in , another common pathogen with a related system, yet only as antagonists. This result not only revealed one of the most potent inhibitors known in but also highlighted differences in the mechanisms of agonism and antagonism between these related bacteria. Finally, our investigations reveal unexpected inhibitory behavior for certain agonists at sub-activating concentrations, an observation that can be leveraged for the design of future probes with enhanced potencies. Together, these peptides provide a powerful tool set to interrogate the role of QS in infections and in pathogenicity in general.
病原体利用化学信号转导过程,即群体感应(QS),形成强大的生物膜并引起人类感染。关于 QS 在 中的作用仍有许多问题,因为它利用这种细胞间通讯途径来负调控和正调控毒力特性。在此,我们报告了能够进行有效超激活和完全抑制的合成多群组 辅助基因调控器()QS 系统的激动剂和拮抗剂。这些大环肽在三个主要的 特异性组中保持完全效力,并且它们的活性可以通过细微的残基特异性结构变化从激动剂“模式切换”为拮抗剂。我们描述了这些非天然肽的设计和合成,并证明它们可以显著减少非生物表面上的生物膜形成,强调了作为阻断 毒力的途径的 激动作用的潜力。此外,我们表明,两种 激动剂和拮抗剂在另一种常见的具有相关 系统的病原体 中都是有效的,但仅作为拮抗剂。该结果不仅揭示了 中已知的最有效的 抑制剂之一,而且还突出了这些相关细菌中 QS 激动和拮抗作用的机制存在差异。最后,我们的研究揭示了某些 激动剂在亚激活浓度下的意外抑制行为,这一观察结果可用于设计具有增强效力的未来探针。总之,这些肽提供了一个强大的工具集,可以探究 QS 在 感染和一般 致病性中的作用。