Bacterial Second Messenger Mediated Virulence Regulation in Streptococcus mutans

细菌第二信使介导的变形链球菌毒力调节

• 批准号: 10227894
• 负责人: Hui Wu
• 金额: $ 31.47万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227894
• 关键词: Address; Adenosine Monophosphate; Adenylate Cyclase; Animal Model; Antibiotic Resistance; Bacteria; Bacterial Infections; Basic Science; Binding; Biochemical; Biological Assay; Cell physiology; Chronic; Code; Communicable Diseases; Complex; Crystallization; Dental Models; Dental caries; Development; Dietary Sugars; Disease; Enzymes; Etiology; Exhibits; Future; Gene Silencing; Genes; Genetic; Glucans; Glucosyltransferases; Growth; In Vitro; Incidence; Infectious Agent; Lactic acid; Lead; Link; Mediating; Microbial Biofilms; Microbiology; Modeling; Molecular; Nature; Oral cavity; Oxidative Stress; Pathogenesis; Pathway interactions; Periodicity; Pharmaceutical Chemistry; Phenotype; Play; Production; Property; Public Health; Publishing; Rattus; Regulation; Research Personnel; Resistance to infection; Role; Scheme; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Molecule; Staphylococcus aureus; Streptococcus; Streptococcus mutans; Streptococcus pneumoniae; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Tooth Demineralization; Virulence; Virulence Factors; Virulent; base; biological adaptation to stress; combat; dental agent; dental biofilm; design; drug discovery; effective therapy; fitness; in vivo; insight; microbial; novel; novel strategies; oral bacteria; oral streptococci; pathogen; phosphoric diester hydrolase; prevent; receptor; receptor binding; response; small molecule; structural biology; therapeutic target; tooth surface; trait

ABSTRACT Recently a new bacterial second messenger termed cyclic di-adenosine monophosphate(c-di-AMP) has been identified and shown to play vital roles in diverse bacterial cellular processes. C-di-AMP is essential in many Gram-positive pathogens including Staphylococcus aureus and Streptococcus pneumoniae. We and others have found that c-di-AMP is not essential in Streptococcus mutans, an important etiological agent of dental caries (cavity), but regulates cariogenic biofilm formation, bacterial stress responses, and dynamic polymicrobial interactions that are crucial for S. mutans fitness and virulence. Little is known about the role of c-di-AMP signaling pathways that modulate distinct and conserved virulent properties found in S. mutans and other pathogens. In this proposal, we use S. mutans as a model to elucidate virulence regulation mediated by this emerging signaling molecule. Inactivation of the gene coding for c-di-AMP producing enzyme reduced bacterial colonization and virulence in a rat model of dental caries, demonstrating a critical role of c-di-AMP in S. mutans virulence. Moreover, c-di-AMP-mediated virulence networks are integrated into a key response regulator VicR- modulated signaling through a newly identified c-di-AMP binding receptor (CabPA). These novel findings led us to hypothesize that c-di-AMP regulates biofilm formation and other virulence properties via multiple new pathways, which represent major potential therapeutic targets to develop novel and selective anti-virulence compounds. Two specific aims are proposed to test the hypothesis: 1) To elucidate c-di-AMP and its receptor CabPA mediated signaling pathways that modulate the biofilm formation and other virulence properties; 2) To develop new small molecule compounds that modulate S. mutans virulence by targeting the c-di-AMP producing enzyme. The proposal would allow us to identify new signaling components and unknown dynamic interactions in c-di-AMP-mediated pathways responsible for the biofilm formation, oxidative stress, and bacterial competitiveness, and uncover potential therapeutic targets, which would facilitate the future development of new small molecule compounds that are amenable for drug discovery. The proposal tests a new hypothesis that links c-di-AMP signaling to VicR-mediated expression of a variety of virulence genes through a distinct c-di-AMP receptor, and documents non-essential nature of c-di-AMP signaling in S. mutans, and explores the translational potential using anti-virulence strategy. Successful completion of this application will have a direct impact on public health as dental caries and other infectious conditions are widespread due to antibiotic resistance and lack of effective treatment options. Development of anti-S. mutans virulence strategy in the proposal is also relevant to devise species-specific anti-virulence strategy targeting significant pathogens such as S. aureus and S. pneumoniae, which should open a new venue to the design of new anti-infectious agents to combat microbial infection and antibiotic resistance.

摘要 最近，一种新的细菌第二信使，称为环二磷酸腺苷（c-di-AMP）， 鉴定并显示在不同的细菌细胞过程中发挥重要作用。C-di-AMP在许多情况下是必不可少的 革兰氏阳性病原体包括金黄色葡萄球菌和肺炎链球菌。我们和其他人 已经发现c-di-AMP在变形链球菌中不是必需的，变形链球菌是龋齿的重要病原体 （腔），但调节致龋生物膜的形成，细菌应激反应，和动态多微生物 对S.变形菌适应性和毒力。对c-di-AMP的作用知之甚少 信号通路，调节在S.变形菌和其他 病原体在这个例子中，我们使用S。作为一个模型，以阐明毒力调节介导的这一点 新兴信号分子编码c-di-AMP产生酶的基因的失活减少细菌 在大鼠龋齿模型中的定殖和毒力，证明了c-di-AMP在S.变形 毒性此外，c-di-AMP介导的毒力网络被整合到一个关键的反应调节因子VicR中。 通过新鉴定的c-di-AMP结合受体（CabPA）调节信号传导。这些新发现让我们 假设c-di-AMP通过多种新的途径调节生物膜形成和其他毒力特性， 途径，代表了开发新型和选择性抗病毒的主要潜在治疗靶点 化合物.本论文的主要目的是：1）阐明c-di-AMP及其受体 CabPA介导的调节生物膜形成和其他毒力特性的信号传导途径; 2） 开发新的小分子化合物来调节S.通过靶向产生c-di-AMP的变形菌毒力 酵素该提案将使我们能够识别新的信号成分和未知的动态相互作用 在c-di-AMP介导的途径中，负责生物膜形成、氧化应激和细菌 竞争力，并发现潜在的治疗靶点，这将有助于未来开发新的 适合于药物发现的小分子化合物。该提案测试了一个新的假设， 通过不同的c-di-AMP信号传导至VicR介导的多种毒力基因的表达 受体，并记录了S.变种人，并探讨了翻译 可能使用抗毒力策略。成功完成此应用程序将直接影响 由于抗生素耐药性，龋齿和其他传染病很普遍， 缺乏有效的治疗方案。抗S.变形杆菌毒力策略的建议也是 相关的设计针对重要病原体，如S.金黄色葡萄球菌和 S.肺炎，这应该打开一个新的场地，设计新的抗感染剂，以打击微生物 感染和抗生素耐药性。