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环二腺苷一磷酸(c-di-amp)被发现 被发现并被证明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 (空洞)，但调节致龋性生物膜的形成、细菌应激反应和动态多聚菌素 对变形链球菌的适合性和毒力至关重要的相互作用。人们对c-di-amp的作用知之甚少 在变形链球菌和其他细菌中发现的调节不同和保守的毒力特性的信号通路 病原体。在这项建议中，我们使用变形链球菌作为模型来阐明由该基因介导的毒力调节。 新兴的信号分子。C-二-AMP产生酶编码基因失活还原细菌 C-diAMP在变形链球菌中的关键作用在龋齿大鼠模型中的定植和毒力 致命性。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-2中。 通过新发现的c-di-AMP结合受体(CabPA)调节信号。这些新奇的发现使我们 假设c-diAMP通过多个新的新基因调控生物膜的形成和其他毒力特性 代表开发新的和选择性抗毒力的主要潜在治疗靶点的途径 化合物。提出了两个特定的目的来检验这一假说：1)阐明c-diamp及其受体。 CabPA介导的信号通路，调节生物膜的形成和其他毒力特性；2) 通过靶向c-diAMP的产生来开发新的小分子化合物来调节变形链球菌的毒力 酵素。该提案将使我们能够识别新的信令组件和未知的动态交互 在c-di-AMP介导的生物被膜形成、氧化应激和细菌途径中 竞争力，并发现潜在的治疗靶点，这将促进新的 可用于药物发现的小分子化合物。该提案测试了一种新的假设，即 C-di-AMP通过不同的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c-di-AMP信号在变形链球菌中的非本质性质，并探索了 有潜力使用抗毒力策略。成功完成这项申请将直接影响到 由于抗生素耐药性和其他感染性疾病，龋齿和其他传染病等公共卫生问题普遍存在 缺乏有效的治疗选择。抗S抗体的研究进展变种人的毒力策略也在提案中 与针对金黄色葡萄球菌和金黄色葡萄球菌等重要病原体制定针对特定物种的抗毒力战略有关 肺炎链球菌，这应该为设计新的抗感染剂来对抗微生物开辟了一个新的场所 感染和抗生素耐药性。