Developing multispecies quorum-sensing modulators based on the Streptococcus mitis competence-stimulating peptide.
Developing multispecies quorum-sensing modulators based on the Streptococcus mitis competence-stimulating peptide.
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DOI：
10.1016/j.jbc.2023.105448
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发表时间：
2023-12
影响因子：
4.8
通讯作者：
Tal-Gan, Yftah
中科院分区：
文献类型：
--
作者：
Milly, Tahmina A.;Renshaw, Clay P.;Tal-Gan, Yftah
细菌利用群体感应（QS）来协调许多群体行为。因此，QS作为一种潜在的手段，在不引入耐药性发展的选择性压力的情况下减弱细菌传染性，引起了人们的极大关注。一种人类共栖的链球菌，作为一种流行的人类病原体肺炎链球菌的遗传多样性储存库。S. mitis具有典型的comABCDE能力调节QS电路；然而，能力刺激肽（CSP）在S. mittis中负责QS激活和能力调节QS回路的调节作用尚不清楚。我们着手描述S. mitis的能力调控QS回路，包括确认原生CSP信号的身份，评估控制CSP与组氨酸激酶受体ComD相互作用导致ComD激活的分子机制，以及定义能力调控QS回路在启动各种S. mitis表型中的调节作用。我们的分析揭示了CSP信号的重要构效关系，并促进了新型基于CSP的QS调制器的开发。我们的分析还揭示了能力调控参与调节能力发展和生物膜的形成。此外，我们的分析表明，本地链球菌CSP信号可以调节肺炎链球菌的QS反应。利用这种串扰，我们开发了一种多物种QS调节剂，可以高效激活肺炎球菌ComD受体和S. mitis ComD-2受体。本文鉴定的新型支架可用于评价时间QS调制对S. mitis的影响，因为它栖息在其自然生态位中。
Bacteria utilize quorum sensing (QS) to coordinate many group behaviors. As such, QS has attracted significant attention as a potential mean to attenuate bacterial infectivity without introducing selective pressure for resistance development. Streptococcus mitis, a human commensal, acts as a genetic diversity reservoir for Streptococcus pneumoniae, a prevalent human pathogen. S. mitis possesses a typical comABCDE competence regulon QS circuitry; however, the competence-stimulating peptide (CSP) responsible for QS activation and the regulatory role of the competence regulon QS circuitry in S. mitis are yet to be explored. We set out to delineate the competence regulon QS circuitry in S. mitis, including confirming the identity of the native CSP signal, evaluating the molecular mechanism that governs CSP interactions with histidine kinase receptor ComD leading to ComD activation, and defining the regulatory roles of the competence regulon QS circuitry in initiating various S. mitis phenotypes. Our analysis revealed important structure-activity relationship insights of the CSP signal and facilitated the development of novel CSP-based QS modulators. Our analysis also revealed the involvement of the competence regulon in modulating competence development and biofilm formation. Furthermore, our analysis revealed that the native S. mitis CSP signal can modulate QS response in S. pneumoniae. Capitalizing on this crosstalk, we developed a multispecies QS modulator that activates both the pneumococcus ComD receptors and the S. mitis ComD-2 receptor with high potencies. The novel scaffolds identified herein can be utilized to evaluate the effects temporal QS modulation has on S. mitis as it inhabits its natural niche.
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