Identification of highly potent competence stimulating peptide-based quorum sensing activators in Streptococcus mutans through the utilization of N-methyl and reverse alanine scanning
Identification of highly potent competence stimulating peptide-based quorum sensing activators in Streptococcus mutans through the utilization of N-methyl and reverse alanine scanning
复制标题
DOI：
10.1016/j.bmcl.2019.01.029
复制
发表时间：
2019-03-15
影响因子：
2.7
通讯作者：
Tal-Gan, Yftah
中科院分区：
文献类型：
--
作者：
Bikash, Chowdhury Raihan;Tal-Gan, Yftah
群体感应 (QS) 控制变形链球菌的致病行为，变形链球菌是龋齿的主要原因。变形链球菌使用能力刺激肽 (CSP) 来控制突变蛋白的产生，突变链球菌利用这种细菌素在混合生物膜环境中击败不同的共生细菌。在这项研究中，我们对基于 18-CSP 的支架进行了 N-甲基扫描，该支架缺少前两个被证明是可有可无的氨基酸残基，以获得关于主链酰胺质子在 CSP 和 ComD 受体相互作用中的作用的重要机制见解。然后，我们利用反向丙氨酸方法开发具有增强活性的基于 CSP 的类似物。使用种间抑制测定，发现两种最有效的类似物可诱导亚纳摩尔浓度的细菌素产生。总体而言，我们的分析表明 18-CSP 序列尚未优化，可以通过用丙氨酸替换多个位置来改进。我们的结果进一步表明，变形链球菌 18-CSP 中的疏水残基参与受体结合和激活。
Quorum sensing (QS) controls the pathogenic behavior of Streptococcus mutans, a primary cause of dental caries. S. mutans uses the competence stimulating peptide (CSP) to control mutacin production, a bacteriocin utilized by S. mutans to outcompete different commensal bacteria in mixed biofilm environments. In this study, we performed an N-methyl scan of an 18-CSP-based scaffold lacking the first two amino acid residues that were shown to be dispensable, to gain important mechanistic insight as to the role of backbone amide protons in the interaction between CSP and the ComD receptor. We then utilized the reverse alanine approach to develop CSP-based analogs with enhanced activities. The two most potent analogs were found to induce bacteriocin production at sub-nanomolar concentration using an interspecies inhibition assay. Overall, our analysis revealed that the 18-CSP sequence is not optimized and can be improved by replacement of multiple positions with alanine. Our results further suggest that the hydrophobic residues in S. mutans 18-CSP are involved in both receptor binding and activation.