Streptococcus pneumoniae is an opportunistic human pathogen that utilizes the competence regulon, a quorum-sensing circuitry, to acquire antibiotic resistance genes and initiate its attack on the human host. Interception of the competence regulon can therefore be utilized to study S. pneumoniae cell-cell communication and behavioral changes, as well as attenuate S. pneumoniae infectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in both S. pneumoniae specificity groups with activities at the low nanomolar range. Structural analysis of lead analogs provided important insights as to the molecular mechanism that drives CSP receptor binding and revealed that the pan-group cyclic CSPs exhibit a chimeric hydrophobic patch conformation that resembles the hydrophobic patches required for both ComD1 and ComD2 binding. Moreover, the lead cyclic dnCSP, CSP1-E1A-cyc(Dap6E10), was found to possess superior pharmacological properties, including improved resistance to enzymatic degradation, while remaining nontoxic. Lastly, CSP1-E1A-cyc(Dap6E10) was capable of attenuating mouse mortality during acute pneumonia caused by both group 1 and group 2 S. pneumoniae strains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold against S. pneumoniae infections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.

中文翻译：

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设计对肺炎链球菌具有泛群群体感应抑制活性的循环能力刺激肽（CSP）类似物。


肺炎链球菌是一种机会性人类病原体，它利用能力调节子（一种群体感应电路）来获取抗生素抗性基因并启动对人类宿主的攻击。因此，能力调节子的拦截可用于研究肺炎链球菌细胞间通讯和行为变化，以及减弱肺炎链球菌的感染性。在此，我们报告了环状显性失活能力刺激肽（dnCSP）类似物的设计和合成，该类似物能够拦截肺炎链球菌特异性组中的能力调节子，其活性在低纳摩尔范围内。先导类似物的结构分析提供了关于驱动 CSP 受体结合的分子机制的重要见解，并揭示了泛基团环状 CSP 表现出嵌合疏水斑块构象，类似于 ComD1 和 ComD2 结合所需的疏水斑块。此外，主要的环状 dnCSP CSP1-E1A-cyc(Dap6E10) 被发现具有优异的药理学特性，包括提高对酶降解的抵抗力，同时保持无毒。最后，CSP1-E1A-cyc(Dap6E10)能够降低由第1组和第2组肺炎链球菌菌株引起的急性肺炎期间的小鼠死亡率。因此，这种环状泛基团 dnCSP 是一种很有前途的抗肺炎链球菌感染的药物先导支架，可以单独给药或用于联合治疗，以增强现有抗菌药物的效果。