Targeting Oral Biofilms with 2-Aminoimidazole/Triazole Conjugates

使用 2-氨基咪唑/三唑缀合物靶向口腔生物膜

• 批准号: 8448580
• 负责人: Angela Marie Pollard
• 金额: $ 49.96万
• 依托单位: AGILE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448580
• 关键词: Acute; Adult; Affect; Anatomy; Bacteria; Biological Assay; Biological Factors; Child; Clinical; Clinical Research; Common Cold; Communities; Data; Dental caries; Development; Disease; Dose; Drug Formulations; Economically Deprived Population; Economics; Effectiveness; Environment; Eukaryotic Cell; Excision; Frequencies; Gingivitis; Gnotobiotic; Goals; Growth; Healthcare; Human; In Vitro; Incidence; Individual; Lead; Length; Lymphoma; Measurement; Measures; Microbial Biofilms; Modeling; Mouth Diseases; Mus; Oral; Oral cavity; Phase; Population; Preclinical Testing; Prevalence; Production; Rattus; Resistance; Risk; Route; Safety; Saliva; Science; Solutions; Streptococcus gordonii; Streptococcus mutans; Surface; Technology; Testing; Time; Tooth Tissue; Tooth structure; Topical application; Toxic effect; Treatment Protocols; Triazoles; antimicrobial; antimicrobial drug; base; chemical synthesis; commercialization; cytotoxic; genotoxicity; improved; in vivo; in vivo Model; irritation; killings; large scale production; lead exposure; liquid chromatography mass spectrometry; marine organism; meetings; oral bacteria; oral biofilm; oral care; oral irritation; oral tissue; pathogenic bacteria; phase 1 study; research clinical testing; restraint; scale up; small molecule

DESCRIPTION (provided by applicant): Dental caries is one of the most prevalent diseases in the U.S. with 85% of adults and the majority of children having been treated for at least one incidence. While this disease impacts all individuals, it is especially an issue for those of low economic status who have limited access to professional oral care. Dental caries is attributed to the presence of the acidogenic bacterium Streptococcus mutans within biofilms, or plaque, on oral surfaces. Biofilms are surface-attached communities of bacteria that are surrounded by a protective matrix. Bacteria in biofilms are upwards of 1000 times more resistant to currently used antimicrobials than free-floating bacteria. As such, antimicrobials used in oral rinses do not effectively eliminate biofilms; therefore, plaque continues to accumulate, resulting in dental caries. Based on the prevalence and economic disparity of the disease, an affordable, over-the-counter (OTC), widely-distributed solution to plaque removal is needed. In Phase I, Agile Sciences identified five lead anti-biofilm molecules that are effective at dispersing oral biofilms that cause dental caries. These "Agilyte"" molecules are derived from a natural product that controls biofouling of a marine organism. The lead compounds are able to selectively inhibit and disperse biofilms of S. mutans, while not affecting commensal Streptococcal species, S. gordonii and S. sanguinis. Compound efficacy was demonstrated under growth conditions that mimic saliva flow within the oral environment. The lead compounds are non-cidal to bacteria and not cytotoxic to eukaryotic cells at active concentrations. The compounds are also able to disperse multi-species biofilms formed by human saliva on a tooth-like surface. Treatments of saliva-derived biofilms with current OTC oral rinses revealed that the AgilyteTM compounds are able to increase the efficacy of the active ingredients by >2-fold, and this enhancement of oral rinse activity is seven times greater under flow conditions that are more representative of the oral environment. In this Phase II project, we will use in vitro and in vivo analyses to further develop these lead compounds as anti-biofilm additives for OTC oral rinses. In Aim 1, toxicity profiles of the lead compounds will be determined. In Aim 2, an in vivo model of oral colonization will be used to determine if the biofilm reduction capabilities seen in vitro translat to the ability to decrease plaque load in vivo within formulation. A single lead compound identified in Aim 2 will be evaluated in Aim 3 for stability within formulation and will undergo synthetic optimization for large- scale production. The major milestone to be achieved in this Phase II project will be identification of a lead molecule that is non-toxic, active in vivo, and cn be synthesized on a large scale for commercial production. In Phase III, the formulated Agilyte" oral rinse will undergo additional preclinical and clinical testing that will facilitate commercialization of an OTC oral rinse product that is highly effective at removing pathogenic biofilms from teeth. This product has the potential to improve personal oral healthcare, thereby decreasing the incidence of dental caries, particularly for those of low economic status that are most affected by the disease.

描述（由申请人提供）：龋齿是美国最普遍的疾病之一，其中85％的成年人和大多数儿童接受了至少一个发病率的治疗。尽管这种疾病会影响所有人，但对于那些经济状况低下的人获得专业口腔护理的人来说，这尤其是一个问题。龋齿归因于生物膜或斑块上的酸性细菌在口腔表面上的存在。生物膜是被保护基质包围的细菌表面附着的群落。生物膜中的细菌比自由浮动细菌对当前使用的抗菌药物的耐药性高1000倍。因此，口服冲洗中使用的抗菌剂不 有效消除生物膜；因此，斑块继续积聚，导致龋齿。根据疾病的患病率和经济差异，需要一种负担得起的非处方（OTC），被广泛分布的解决方案以清除牙菌斑。 在第一阶段，敏捷科学鉴定出有效分散口服生物膜的五个铅抗生物胶片分子 这会导致龋齿。这些“ agilyte”分子是从控制海洋生物生物染色的天然产物中得出的。铅化合物能够选择性地抑制和分散突变链球菌的生物膜，同时不影响康多的链球菌物种，在戈尔多尼和sanguinis中影响了sanguinis s. sanguinis。复合效率。在活性浓度下对细菌而非细胞毒性对真核细胞。在流动条件下，口腔冲洗活性的增强是在此阶段II阶段的七倍。在AIM 2中识别的单个铅化合物在体内降低体内的生物膜还原能力。在第三阶段的商业生产大规模。该产品有可能改善个人口腔医疗保健，从而降低龋齿的发病率，尤其是对于受疾病影响最低的经济状况低下的发病率。