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Small molecule inhibitors of cariogenic biofilms

致龋生物膜小分子抑制剂

基本信息

批准号：
10264098
负责人：
Christian Corey Melander
金额：
$ 39.22万
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：
2020-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264098
关键词：
Acids American Animal Model Antibiotics Bacteria Biochemical Biochemical Pathway Biology Caries prevention Chemicals Clinical Research Clinical Trials Collaborations Communicable Diseases Communities Complex Consumption Dental Enamel Dental Models Dental caries Dentists Development Diet Dietary Factors Etiology Evaluation Family Funding Future Gene Expression Regulation General Population Genetic Goals Gram-Negative Bacteria Gram-Positive Bacteria Host Defense Human In Vitro Lactic acid Lead Lesion Life Style Manuscripts Microbial Biofilms Microbial Genetics Modeling Molecular Molecular Target Odontogenesis Oral health Pathway interactions Positioning Attribute Prevention strategy Property Proteins Publishing Rattus Reagent Resistance Scheme Scientist Signal Transduction Streptococcus mutans Structural Biologist Structure Structure-Activity Relationship Sucrose Systems Biology Therapeutic Tooth Demineralization Vaccines Virulence analog anticaries bacterial fitness base cariogenic bacteria clinical translation conventional therapy cost dental biofilm design drug discovery dysbiosis early childhood effective therapy experience fitness human disease human old age (65+)improved in silico in vivo interdisciplinary approach marine natural product microbial community novel oral bacteria oral commensal oral microbial community oral streptococci physical insult pre-clinical prevent response scaffold small molecule small molecule inhibitor tooth surface transcription factor treatment strategy

项目摘要

Abstract Dental caries (tooth decay) is the most prevalent infectious disease afflicting American Public. Biofilm formation is crucial for the development of dental caries induced by cariogenic bacteria. Streptococcus mutans is a model cariogenic bacterium that has adapted to the biofilm lifestyle. Bacteria within a biofilm are extremely resistant to traditional antibiotics and host defense; therefore development of new classes of anti-biofilm reagents that interfere with the biofilm formation and development by cariogenic bacteria is necessary and critical for the treatment and prevention of dental caries. The most potent and versatile class of molecules with anti-biofilm properties are those derived from the 2-aminoimidazole (2-AI) scaffold discovered by the Melander group from natural marine products. The 2-AI derivative is capable of inhibiting and dispersing diverse biofilms formed by Gram-negative and Gram-positive bacteria. In the last funding cycle, we have made great progress, and identified and characterized two distinct 2-AI derivatives that either inhibit or disperse S. mutans cariogenic biofilms specifically. The lead compounds do not affect biofilm formation by commensal oral streptococci. Our studies have shown that one 2-AI derivative selectively targets a response regulator that modulates S. mutans biofilm, fitness and virulence. The compound inhibits biofilm formation in vitro and bacterial virulence in vivo in the complex microbial community, indicating it has great therapeutic potential. Another derivative we identified selectively disperses preformed S. mutans biofilms in vitro and inhibits bacterial colonization and virulence in vivo. The dispersion activity is not mediated by any known biofilm pathway, suggesting a novel underlying mechanism. The goal of our current proposal is to further explore these two new classes of small molecules, define their modes of action and develop more potent, selective chemical probes to dissect small molecules- directed gene regulation and signaling that are key to biofilm development. Two specific aims are proposed: Specific Aim 1: Explore molecular mechanisms of selective targeting of the response regulator of cariogenic bacteria by the 2-AI derivative and use both structure-activity relationship studies, and structure-based drug discovery schemes to enlighten the design and the development of more potent and selective chemical probes to enhance anti-cariogenic activity. Specific Aim 2: Identify molecular targets of the potent small molecule that disperses cariogenic S. mutans biofilms and determine the underlying mechanism of the biofilm dispersion. An interdisciplinary team among microbiologists, medicinal chemists, structural biologists, animal model experts, and dentist scientists will continue their productive collaborations, which should unravel molecular mechanisms how lead compounds selectively inhibit and disperse cariogenic biofilms and facilitate the development of new anti-caries strategies. The application will have a direct impact on the oral health of the general public since the lead compounds have great therapeutic potentials in preventing or treating dental caries.

摘要