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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.

摘要