Structure Activity Relationship Study of the XIP Quorum Sensing Pheromone in Streptococcus mutans Reveal Inhibitors of the Competence Regulon.
Structure Activity Relationship Study of the XIP Quorum Sensing Pheromone in Streptococcus mutans Reveal Inhibitors of the Competence Regulon.
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DOI：
10.1021/acschembio.0c00650
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发表时间：
2020-10-16
影响因子：
4
通讯作者：
Tal-Gan Y
中科院分区：
文献类型：
--
作者：
Bikash CR;Tal-Gan Y
致龋齿病原体变形链球菌通过两种肽信息素、能力刺激肽 (CSP) 和 comX 诱导肽 (XIP) 协调遗传转化能力。 CSP由comCDE系统感知并间接诱导能力，而XIP由comRS系统感知并直接诱导能力。在化学成分确定的培养基 (CDM) 中，被寡肽通透酶吸收后，XIP 与胞质受体 ComR 相互作用，形成 XIP::ComR 复合物，激活 comX 的表达，comX 是启动晚期感受态基因转录的替代 sigma 因子。在本研究中，我们着手确定 XIP::ComR 相互作用的分子机制。为此，我们对 XIP 信息素中的氨基酸残基进行了系统替换，并评估了突变类似物调节 CDM 能力调节子的能力。我们能够确定对 ComR 结合和激活很重要的结构特征。我们对结构-活性关系的见解引导我们构建了多种基于 XIP 的 comRS 通路抑制剂。此外，当 comCDE 和 comRS 分别用 CSP 和 XIP 刺激时，基于 XIP 的先导抑制剂能够维持抑制活性。最后，使用表型测定来强调基于 XIP 的抑制剂减弱变形链球菌致病性的潜力，并验证这些化合物对能力调节子内 comRS 途径的特异性。本研究中开发的基于 XIP 的抑制剂可用作设计和开发针对变形链球菌感染的潜在疗法的先导支架。
The dental cariogenic pathogen Streptococcus mutans coordinates competence for genetic transformation via two peptide pheromones, competence stimulating peptide (CSP) and comX-inducing peptide (XIP). CSP is sensed by the comCDE system and induces competence indirectly whereas, XIP is sensed by the comRS system and induces competence directly. In chemically defined media (CDM), after uptake by oligopeptide permease, XIP interacts with the cytosolic receptor ComR to form the XIP::ComR complex that activates the expression of comX, an alternative sigma factor that initiates the transcription of late-competence genes. In this study, we set out to determine the molecular mechanism of XIP::ComR interaction. To this end, we performed systematic replacement of the amino acid residues in the XIP pheromone and assessed the ability of the mutated analogs to modulate the competence regulon in CDM. We were able to identify structural features that are important to ComR binding and activation. Our structure-activity relationship insights led us to construct multiple XIP-based inhibitors of the comRS pathway. Furthermore, when comCDE and comRS were both stimulated with CSP and XIP, respectively, a lead XIP-based inhibitor was able to maintain the inhibitory activity. Lastly, phenotypic assays were used to highlight the potential of XIP-based inhibitors to attenuate pathogenicity in S. mutans and to validate the specificity of these compounds to the comRS pathway within the competence regulon. The XIP-based inhibitors developed in this study can be used as lead scaffolds for the design and development of potential therapeutics against S. mutans infections.
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