Designing cyclic competence-stimulating peptide (CSP) analogs with pan-group quorum-sensing inhibition activity in Streptococcus pneumoniae.
Designing cyclic competence-stimulating peptide (CSP) analogs with pan-group quorum-sensing inhibition activity in Streptococcus pneumoniae.
复制标题
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。
DOI：
10.1073/pnas.1915812117
复制
发表时间：
2020
影响因子：
11.1
通讯作者：
Tal-Gan,Yftah
中科院分区：
文献类型：
--
作者：
Yang,Yifang;Lin,Jingjun;Harrington,Anthony;Cornilescu,Gabriel;Lau,GeeW;Tal-Gan,Yftah
肺炎链球菌（Streptococcus pneumoniae）是一种机会致病菌，它利用感受态调节子（competence regulon），一种群体感应电路，获得抗生素抗性基因并启动其对人类宿主的攻击。因此，可以利用能力调节子的拦截来研究S。肺炎细胞通讯和行为改变，以及衰减。肺炎传染性在此，我们报告的设计和合成的环状显性负性竞争力刺激肽（dnCSP）类似物能够拦截的感受态调节子在bothS。肺炎特异性组的活性在低纳摩尔范围内。铅类似物的结构分析提供了重要的见解，驱动CSP受体结合的分子机制，并揭示了泛组环状CSP表现出嵌合疏水补丁构象，类似于ComD 1和ComD 2结合所需的疏水补丁。此外，发现先导环状dnCSP，CSP 1-E1 A-cyc（Dap 6 E10）具有上级药理学性质，包括改善的对酶降解的抗性，同时保持无毒。最后，CSP 1-E1 A-cyc（Dap 6 E10）能够减弱由组1和组2S两者引起的急性肺炎期间的小鼠死亡率。肺炎菌株因此，这种环状泛基dnCSP是一种有前途的抗S药物先导支架。这些药物可以单独给药或用于联合治疗以增强当前抗微生物剂的效果。
Streptococcus pneumoniaeis 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 studyS. pneumoniaecell−cell communication and behavioral changes, as well as attenuateS. pneumoniaeinfectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in bothS. pneumoniaespecificity 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 2S. pneumoniaestrains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold againstS. pneumoniaeinfections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.