Unveiling the Importance of Amide Protons in CSP:ComD Interactions in Streptococcus pneumoniae.
Unveiling the Importance of Amide Protons in CSP:ComD Interactions in Streptococcus pneumoniae.
复制标题
DOI：
10.1021/acsmedchemlett.9b00038
复制
发表时间：
2019-04
影响因子：
4.2
通讯作者：
Bimal Koirala;N. R. Phillips;Yftah Tal‐Gan
中科院分区：
文献类型：
--
作者：
Bimal Koirala;N. R. Phillips;Yftah Tal‐Gan
肺炎链球菌是一种机会致病菌，可引起从轻度呼吸道感染到危及生命的疾病，如肺炎、脑膜炎和菌血症。S.肺炎克雷伯氏菌的致病性依赖于17个氨基酸的肽信息素（称为感受态刺激肽（CSP））的作用，所述肽信息素控制感受态调节子，即群体感应（QS）回路。因此，拦截QS可能在治疗肺炎球菌感染方面具有治疗意义，同时避免出现抗生素耐药性。在这项研究中，我们着手评估酰胺质子对CSP活性和代谢稳定性的影响，通过系统的N-甲基化。我们的研究结果表明，大多数酰胺质子的CSP活性是至关重要的，无论是通过与同源受体的直接相互作用或通过稳定的生物活性构象。重要的是，我们鉴定了几种N-甲基CSP类似物，即CSP 1（15）-N-Me-K6和CSP 1（15）-N-Me-F7，它们保留了它们的生物活性，同时表现出增强的代谢稳定性。这些类似物是用于设计具有药物样性质的基于CSP的QS调节剂的特权支架。
Streptococcus pneumoniae is an opportunistic pathogen that can cause diseases ranging from mild respiratory infections to life-threatening conditions such as pneumonia, meningitis, and bacteremia. S. pneumoniae pathogenicity is dependent on the action of a 17-amino acid peptide pheromone, termed competence stimulating peptide (CSP) that controls the competence regulon, a quorum sensing (QS) circuit. Therefore, intercepting QS could have therapeutic implications in treating pneumococcal infections while avoiding emerging antimicrobial resistance. In this study, we set out to evaluate the impact of amide protons on CSP activity and metabolic stability through systematic N-methylation. Our results indicate that the majority of amide protons are critical for CSP activity, either through direct interactions with the cognate receptor or by stabilizing the bioactive conformation. Importantly, we identified several N-methyl CSP analogs, namely, CSP1(15)-N-Me-K6 and CSP1(15)-N-Me-F7, that retain their biological activity while exhibiting enhanced metabolic stability. These analogs are privileged scaffolds for the design of CSP-based QS modulators with drug-like properties.