DISPERSION OF STREPTOCOCCUS MUTANS BIOFILMS BY A NOVEL SMALL MOLECULE

通过新型小分子分散变形链球菌生物膜

• 批准号: 8652185
• 负责人: Sandra Stephanie Garcia
• 金额: $ 4.3万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2015-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652185
• 关键词: Affect; Affinity Chromatography; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Architecture; Bacteria; Biological Assay; Biological Factors; Carbohydrates; Chemicals; Child; Collaborations; Communicable Diseases; Complex; DNA; Data; Dental Enamel; Dental caries; Development; Diet; Dietary Sugars; Disease; Drug Targeting; Excision; Exhibits; Extracellular Protein; Fluorides; Genes; Genetic Transcription; Germ-Free; Glucans; Glucosyltransferases; Goals; HA coating; Image; In Vitro; Incidence; Knock-out; Lactic acid; Laser Scanning Confocal Microscopy; Libraries; Lipids; Maintenance; Marines; Marketing; Mass Spectrum Analysis; Metabolism; Methods; Microbial Biofilms; Modeling; Mouthwash; Oral cavity; Organism; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Porifera; Prevention; Production; Property; Rattus; Resistance; Saliva; Science; Serotyping; Streptavidin; Streptococcus; Streptococcus gordonii; Streptococcus mutans; Structure; Sucrose; Testing; Therapeutic Agents; Tooth structure; Toothpaste; antimicrobial; base; cariogenic bacteria; demineralization; effective therapy; glucosyltransferase B; glucosyltransferase D; in vivo; killings; microorganism; mutant; novel; oral commensal; pathogenic bacteria; prevent; public health relevance; screening; small molecule; small molecule libraries; therapeutic target; tooth surface; transcriptome sequencing

DESCRIPTION (provided by applicant): Dental caries is a costly disease characterized by the demineralization of the enamel, otherwise known as tooth decay. Despite advances in science, dental caries is the most common infectious disease worldwide and is increasing in incidence among young children. The etiologic causative agent of dental caries is Streptococcus mutans. Not only can S. mutans form biofilms readily on the tooth surface, but this bacterium rapidly produces lactic acid from dietary sugars. Dental caries cannot be easily treated with conventional antibiotics as cariogenic bacteria form tenacious biofilms, which are resistant to antibiotics. Current marketed therapies lack sensitivity; they are not species-specific and kill pathogenic species as well as commensal species, which are protective against the formation of pathogenic biofilms. In order to develop a therapeutic agent that is species specific for S. mutans, we constructed a diverse library of small molecules based on the structural motifs of bromoageliferin, a marine sponge product with antibiofilm and antibacterial properties. In a previous study, we utilized the library in a biofilm formation inhibition assay to identify potent small molecules that inhibit S. mutans biofilm formation specifically. Currently, we are redirecting our approach to focus on dispersing established S. mutans biofilms. By screening our library of small molecules with a biofilm dispersion assay, we identified 3F1 as a novel small molecule that selectively disperses S. mutans biofilms. While 3F1 dispersed approximately 50% of S. mutans biofilm, it did not disperse biofilms formed by commensal species Streptococcus sanguinis or Streptococcus gordonii. Confocal laser scanning microscopy images revealed that 3F1 altered the architecture of the biofilm by affecting the exopolymeric matrix, made evident through the reduced amount of exopolysaccharides. Glucosyltransferases (Gtfs) secreted by S. mutans are largely responsible for forming the exopolysaccharides which make up a large proportion of the exopolymeric matrix. The activity of 3F1 was not negated by the absence of the primary Gtf, GtfB, leading us to hypothesize that our small molecule induces the dispersal of S. mutans biofilms by interacting with a potentially unique and unknown mechanism related to the development and production of the exopolymeric matrix, which is necessary for biofilm maturation, structure, or maintenance. The identification of a novel target implicated in biofilm formation in S. mutans could potentially become a therapeutic target for the prevention or treatment of dental caries, while maintaining the commensal populations.

描述（由申请人提供）：龋齿是一种昂贵的疾病，其特征是釉质脱矿，也称为蛀牙。尽管科学进步，龋齿是世界上最常见的传染病，并且在幼儿中的发病率正在增加。龋病的病原体是变形链球菌。不仅可以S。变形杆菌很容易在牙齿表面形成生物膜，但这种细菌从食物中的糖迅速产生乳酸。龋齿不容易用常规抗生素治疗，因为致龋细菌形成对抗生素具有抗性的坚韧生物膜。目前市售的疗法缺乏敏感性;它们不是物种特异性的，并且杀死病原性物种以及病原性物种，其保护免于形成病原性生物膜。为了开发对S.为了鉴定变异株，我们构建了一个基于溴ageliferin结构基序的小分子多样性文库，溴ageliferin是一种具有抗菌膜和抗菌特性的海绵产品。在以前的研究中，我们利用生物膜形成抑制试验中的文库来鉴定抑制S.变形菌生物膜的形成。目前，我们正在重新调整我们的方法，集中精力分散既定的S。变形杆菌生物膜通过用生物膜分散试验筛选我们的小分子文库，我们鉴定了3F 1作为一种选择性分散S.变形杆菌生物膜而3F 1分散了约50%的S.变形链球菌生物膜，它不分散由嗜酸菌种血链球菌或戈登链球菌形成的生物膜。共聚焦激光扫描显微镜图像显示，3F 1通过影响胞外聚合物基质改变了生物膜的结构，通过减少胞外多糖的量而变得明显。葡萄糖基转移酶（Gtfs）是由S.变形杆菌主要负责形成构成大部分外聚合物基质的外多糖。3F 1的活性并不因缺乏主要的Gtf、GtfB而被否定，这使我们假设我们的小分子诱导了S的扩散。通过与与外聚合基质的发育和产生相关的潜在独特和未知的机制相互作用，该外聚合基质是生物膜成熟、结构或维持所必需的。一个新的目标涉及生物膜形成的S。变形杆菌有可能成为预防或治疗龋齿的治疗靶点，同时保持牙菌群。