Determining the mechanism and impact of streptococcal RaS-RiPPs on the human oral microbiome

项目总结 人类口腔微生物群是一组独特的细菌的家园，这些细菌能够影响整个 人类宿主健康：链球菌属。这一群体涉及范围广泛的疾病，从牙科 从龋齿到感染性心内膜炎。它们包括重要的口腔病原体，如致龋链球菌 变种和共生生物，如米氏链球菌。这些重要的口头成员产生一种 大量自由基-S-腺苷蛋氨酸核糖体合成和翻译后修饰多肽 (RAS-RIPPS)。新鉴定的化合物包括丰富的化学结构，并已被发现 抑制其他口腔链球菌的生长，以及调节生产者的行为 他们自己。这项建议的最初目标是阐明RAS-RIPP甘氨酸酶的作用机制 从变形链球菌中分离出来，并检测其对口腔微生物功能的影响。在定义尝试甘氨酸酶 对口腔链球菌和口腔微生物群的作用机制，这项研究将扩大到检查 链球菌产生的其他RAS-RIPPs的生物学意义：链肌动蛋白，猪肌动蛋白，轮肽， 和NxxC家族多肽。虽然这些多肽的化学结构和合成已经确定，但 这些已鉴定的RAS-RIPP的生物学意义尚未被探索。鉴于链球菌的重要地位 SPP.对于人类口腔微生物区系的健康来说，这代表着关于一类 对整体口腔健康有巨大潜在影响的多肽。这项提议旨在创建一个研究平台 用于研究口腔链球菌的Ras-Ripps，确定其功能，并检查功能上的变化 口腔微生物群对其产生的反应。在伊利诺伊大学执行这项研究计划 芝加哥(UIC)将允许候选人成为独立研究人员，并提供 实现候选人职业目标的途径：建立多产和一流的研究 实验室，并在一家大型研究机构获得终身教职。

PROJECT SUMMARY The human oral microbiome is home to a unique group of bacteria with the ability to affect the overall health of the human host: Streptococci spp. This group is involved in a wide range of diseases, from dental caries to infective endocarditis. They include important oral pathogens such as the cariogenic Streptococcus mutans and commensal organisms such as Streptococcus mitis. These important oral members produce a large array of radical-S-adenosylmethionine ribosomally synthesized and post-translationally modified peptides (RaS-RiPPs). The newly identified compounds include a wealth of chemical structures and have been found to inhibit the growth of other oral Streptococci, as well as modulate the behavior of producer organisms themselves. The initial goal of this proposal is to elucidate the mechanism of action of the RaS-RiPP tryglysin from S. mutans, and to examine its impact on the functional oral microbiome. Upon defining tryglysin’s mechanism of action on oral Streptococci and the oral microbiome, this study will be expanded to examine the biological significance of other RaS-RiPPs produced by Streptococci: streptosactin, suisactin, rotapeptides, and NxxC family peptides. While the chemical structure and synthesis of these peptides has been defined, the biological significance of these identified RaS-RiPPs is unexplored. Given the important status of Streptococci spp. to the health of the human oral microbiota, this represents a major gap in knowledge about a class of peptides with huge potential impacts on overall oral health. This proposal aims to create a research platform for studying RaS-RiPPs from oral Streptococci, defining their function, and examining shifts in the functional oral microbiome in response to their production. Executing this research program at the University of Illinois at Chicago (UIC) will allow for the establishment of the candidate as an independent researcher and provide avenues for the achievement of the candidate’s career goals: establishing a productive and first-rate research laboratory and securing a tenured faculty position at a major research institution.