BrpA in Virulence Modulation of Streptococcus mutans

摘要 尽管在预防和治疗方面取得了实质性进展，但通常被称为龋齿的龋齿 或龋齿，仍然是世界上最常见和最昂贵的传染病之一。根据 美国疾病控制与预防中心表示，相关的医疗保健每年花费美国数百亿美元。新颖、全面 有效防治龋病的发病机制需要制定相应的策略。致龋菌形成顽强的 牙齿表面的生物膜称为牙菌斑。在R01 DE019452的支持下，我们拥有超过 过去六年产生了开创性的证据，即生物膜调节蛋白BrPA，一种多功能表面- 相关蛋白在调节变形链球菌细胞膜生物发生和生长中起关键作用 生物膜的形成及其引起龋损的能力。此次竞争性续签的总体目标是 揭示控制BrPA表达的分子机制的复杂性 BrPA如何介导种内和种间生物膜形成的机制，以及探索 靶向BrPA的先导小分子和对变形链球菌毒力的调节。我们将使用 综合方法，包括各种现代分子、生化和生物信息学技术 确定调控BrPA表达的转录和转录后因子， 并确定不同的结合表位，构建配体-蛋白质复合体模型来指导 BrPA的结构和功能分析。此外，我们将使用有机化学和各种 功能测定和体内大鼠龋病模型优化所选铅的有效性和选择性 抑制变形链球菌的小分子，并探索其在新的防腐策略中的潜力。 这项提议的成功实施可能证明是我们对BRPA理解的重大进步 在变形链球菌的病理生理学中，这最终可能应用于其他革兰氏阳性菌中的LCP蛋白 细菌。这些关于小分子的发现有望为发展 防治变形链球菌和人类龋齿的新策略。

SUMMARY Despite substantial progress in prevention and treatment, dental caries, commonly known as tooth decay or cavities, remains one of the most common and costly infectious diseases worldwide. According to the CDC, associated health care costs USA tens of billions of dollars annually. Novel, comprehensive strategies are needed to effectively combat caries pathogenesis. Cariogenic bacteria form tenacious biofilms on the surface of teeth known as dental plaque. Supported by R01 DE019452, we have over the past six years generated seminal evidence that biofilm regulatory protein BrpA, a multi-functional surface- associated protein, plays a critical role in regulation of Streptococcus mutans cell envelope biogenesis and biofilm formation and its ability to cause carious lesions. The overall goals of this competitive renewal are to uncover the complexity of the molecular mechanisms that govern the expression of brpA and the mechanisms how BrpA mediates intra- and inter-species biofilm formation, and to explore the potential of the lead small molecules in targeting BrpA and modulation of S. mutans virulence. We will use an integrative approach including various modern molecular, biochemical and bioinformatics techniques to identify the transcriptional and post-transcriptional factors that govern the regulation of brpA expression, and to determine the different binding epitopes and build the ligand-protein complex model to guide structural and functional analysis of BrpA. In addition, we will use organic chemistry along with various function assays and in vivo rat caries model to optimize the efficacy and selectivity of the selected lead small inhibitory molecules against S. mutans and to explore their potential in novel anticaries strategy. Successful implementation of this proposal could prove to be major advances in our understanding of BrpA in S. mutans pathophysiology, which could ultimately be applied to the LCP proteins in other Gram-positive bacteria. The findings on small molecules are expected to provide a solid foundation for the development of novel strategies against S. mutans and human dental caries.