BrpA in Virulence Modulation of Streptococcus mutans

总结 尽管在预防和治疗方面取得了实质性进展， 或蛀牙，仍然是世界上最常见和最昂贵的传染病之一。根据 疾病预防控制中心，相关的医疗保健费用美国数百亿美元，每年。新颖，全面 需要有效对抗龋齿发病机理的策略。致龋细菌形成顽强 牙齿表面的生物膜称为牙菌斑。在R 01 DE 019452的支持下，我们拥有超过 过去六年中产生的开创性证据表明，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包膜生物发生和 生物膜形成及其引起龋损的能力。本次竞争性更新的总体目标是 揭示了控制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，并探索 在靶向BrpA和调节S.变形菌毒力我们将使用 包括各种现代分子、生物化学和生物信息学技术的综合方法， 鉴定控制brpA表达调节的转录和转录后因子， 确定不同的结合表位，建立配体-蛋白质复合物模型， BrpA结构和功能分析此外，我们将使用有机化学沿着与各种 功能测定和体内大鼠龋齿模型，以优化所选铅的功效和选择性 抗S.并探索其在新的防龋策略中的潜力。 这项建议的成功实施可能会证明我们对BrpA的理解有重大进展 in S.变形杆菌的病理生理学，这最终可以应用于LCP蛋白在其他革兰氏阳性 细菌关于小分子的发现有望为开发 针对S.变形菌和人类龋齿。

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.