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

基本信息

批准号：
10545763
负责人：
Hui Wu
金额：
$ 33.68万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-03 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545763
关键词：
Address Adenylate Cyclase Animal Model Antibiotic Resistance Bacteria Bacterial Infections Basic Science Binding Biochemical Biological Assay Cell physiology Chronic Code Communicable Diseases Complex 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 Structure Structure-Activity Relationship Testing Therapeutic Tooth Demineralization Virulence Virulence Factors Virulent biological adaptation to stress combat dental agent dental biofilm design drug discovery effective therapy empowerment environmental stressor fitness in vivo insight microbial model organism 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 translational potential virulence gene

项目摘要

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称为环状二腺苷单磷酸盐（C-DI-AMP）鉴定并证明在各种细菌细胞过程中起着至关重要的作用。 C-Di-Amp在许多人中至关重要革兰氏阳性病原体，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在链球菌链球菌中不是必不可少的，这是龋齿的重要病因（腔），但调节了富有创粉的生物膜形成，细菌应激反应和动态多菌血症对螺旋链球菌的适应性和毒力至关重要的相互作用。关于C-Di-Amp的作用知之甚少信号通路调节在葡萄链球葡萄球菌和其他病原体。在此提案中，我们使用S. mutans作为模型来阐明由此介导的毒力调节新兴信号分子。编码C-DI-AMP产生酶的基因灭活降低细菌龋齿大鼠模型中的定殖和毒力，证明了C-Di-Amp在S. utans中的关键作用毒力。此外，将C-DI-AMP介导的毒力网络集成到关键响应调节器VICR- 通过新鉴定的C-DI-AMP结合受体（CABPA）调制信号。这些新颖的发现导致我们假设C-DI-AMP通过多个新型调节生物膜形成和其他毒力性能途径，代表了发展新颖和选择性抗病毒的主要潜在治疗靶标化合物。提出了两个具体目的来检验假设：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）到开发新的小分子化合物，通过靶向C-DI-AMP产生，可调节螺旋链球菌的毒力酶。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负责生物膜形成的C-DI-AMP介导的途径中，氧化应激和细菌竞争力，并发现潜在的治疗靶标，这将促进未来的发展适合药物发现的小分子化合物。该提案检验了一个新假设，该假设链接 C-DI-AMP信号传导通过不同的C-DI-AMP对VICR介导的各种毒力基因的表达受体和文献c-di-amp信号在S. mutans中的非必需性质，并探索翻译使用反病毒策略的潜力。成功完成此申请将直接影响公共卫生作为龋齿和其他感染状况，由于抗生素耐药性和缺乏有效的治疗选择。抗S的发展。该提案中的毒力策略也是与设计物种特异性的抗病毒策略有关，以明显的病原体（例如金黄色葡萄球菌和） S.肺炎，该肺炎应为新的反感染药物的设计打开一个新的场所，以对抗微生物感染和抗生素抗性。