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.

抽象的 最近，一种新的细菌第二信使被称为环二腺苷单磷酸（c-di-AMP） 已被鉴定并显示在多种细菌细胞过程中发挥重要作用。 C-di-AMP 在许多方面都是必需的 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 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 （空腔），但调节致龋生物膜形成、细菌应激反应和动态多微生物 对于变形链球菌的适应性和毒力至关重要的相互作用。关于 c-di-AMP 的作用知之甚少 调节在变形链球菌和其他细菌中发现的独特且保守的毒性特性的信号通路 病原体。在本提案中，我们使用变形链球菌作为模型来阐明由此介导的毒力调节 新兴的信号分子。编码 c-di-AMP 产生酶的基因失活减少了细菌 大鼠龋齿模型中的定植和毒力，证明 c-di-AMP 在变形链球菌中的关键作用 毒力。此外，c-di-AMP 介导的毒力网络被整合到关键反应调节因子 VicR- 通过新鉴定的 c-di-AMP 结合受体 (CabPA) 调节信号传导。这些新颖的发现引导我们 假设 c-di-AMP 通过多种新的调节生物膜形成和其他毒力特性 途径，代表开发新型和选择性抗毒力的主要潜在治疗靶点 化合物。提出了两个具体目标来检验该假设：1）阐明 c-di-AMP 及其受体 CabPA 介导的信号通路调节生物膜形成和其他毒力特性； 2) 至 开发新的小分子化合物，通过靶向产生 c-di-AMP 来调节变形链球菌毒力 酶。该提案将使我们能够识别新的信号组件和未知的动态交互 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，这将有助于未来新药的开发 适合药物发现的小分子化合物。该提案测试了一个新假设，该假设将 c-di-AMP 通过独特的 c-di-AMP 信号转导 VicR 介导的多种毒力基因的表达 受体，并记录了变形链球菌中 c-di-AMP 信号传导的非必需性质，并探索了翻译 使用抗病毒策略的潜力。申请的顺利完成将直接影响 由于抗生素耐药性，龋齿和其他传染病广泛存在，公共卫生问题 缺乏有效的治疗方案。抗S的开发。提案中的 mutans 毒力策略还包括 与设计针对重要病原体（例如金黄色葡萄球菌和 肺炎链球菌，这将为设计新型抗感染剂来对抗微生物开辟新的场所 感染和抗生素耐药性。