Click chemistry for novel antimicrobials against periodontal pathogens

描述（由申请人提供）：本申请涉及广泛的挑战领域（06）：使能技术，以及特定的挑战主题，06-DE-104：口腔、牙科和颅面应用的点击化学。牙周病影响了大部分美国公众，超过50%的成年人患有牙龈炎，5-15%患有中度或重度牙周炎。疾病的晚期导致骨吸收和牙齿附着减少。慢性牙周炎是牙齿脱落的主要原因，占该国牙齿死亡率的50-70%，并且与包括糖尿病，心血管疾病和呼吸系统问题在内的全身性疾病有关，并增加了早产低出生体重儿的风险。牙龈炎和牙周炎主要是由牙周区域的错位细菌引起的感染性疾病。没有细菌，疾病消失，虽然一些后遗症，如骨质流失成为不可逆的疾病进展。因此，牙周炎的治疗主要集中在去除和消除引起疾病的龈下细菌。通过刮治和根面平整的物理去除是标准的治疗方法。许多临床研究表明，抗生素治疗作为物理治疗的辅助手段，可有效阻止和逆转疾病进展，尽管抗生素作为唯一治疗方式的疗效尚未得到仔细确定。一般来说，预防牙周病，特别是在早期阶段，不仅对整体健康很重要，而且还可以间接地降低总的医疗保健费用。因此，设计和验证新的非手术干预和预防牙周病的策略是一个重大的卫生保健挑战。鉴于这种疾病的主要细菌感染性质，改进的抗生素必须在这种努力中发挥核心作用。目前使用的抗生素大多是全身给药的，这可能具有严重的副作用，特别是抗生素相关的腹泻，这妨碍了牙周病早期的常规使用。牙周区域中细菌的有限解剖学存在为局部抗生素治疗提供了自身，并且抗生素凝胶已被使用并取得了一些成功。然而，需要小体积的管理，结合有限的效力和抗菌目标特异性的可用抗生素，可能是限制因素，实现充分的临床潜力的局部抗生素在牙周炎。该项目的总体目标是开发一系列新的抗生素，这些抗生素对与慢性牙周炎相关的主要细菌种类具有显著提高的抗菌效力和选择性。基于其治疗牙周炎的有效性，我们将采用甲硝唑作为先导化合物，通过点击化学方法合成结构多样的硝基杂环化合物库。通过全面的抗微生物和急性毒性测试，我们预计将确定几种有前途的抗生素，它们在牙周炎和生物膜条件下对最重要的牙周病细菌具有改善的活性，并且在人体细胞中没有急性毒性。这样的化合物，特别是当局部施用时，具有显著推进牙周病的治疗选择的巨大潜力，从而有助于实现在大部分美国公众中防止不必要的牙齿死亡和重要的全身性疾病恶化的最终目标。此外，及时和具有成本效益的干预与更有效的抗生素，特别是局部使用时，有可能推迟，并可能消除在某些情况下，需要昂贵的牙周炎手术治疗。牙周病是一种主要由牙周组织中的错位细菌引起的感染性疾病，影响了美国大部分公众。物理去除致病细菌是标准疗法，但抗生素作为抗生素具有明显的有益效果。该项目将开发新的抗生素，其对引起慢性牙周炎的主要细菌物种的抗菌效力和选择性显着提高，这将有助于显着推进牙周疾病的治疗选择和结果。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06): Enabling Technologies, and specific Challenge Topic, 06-DE-104: Click Chemistry for Oral, Dental and Craniofacial Applications. Periodontal diseases affect a large segment of the American public, with over 50% of adults having gingivitis and 5-15% having a moderate or severe form of periodontitis. Advanced stages of the disease lead to bone resorption and diminished tooth attachment. Chronic periodontitis is the leading cause of tooth loss, accounting for 50-70% of tooth mortality in this country, and has been linked to systemic diseases including diabetes, cardiovascular disease, and respiratory problems, and increased risk of giving birth to preterm low-birth-weight infants. Gingivitis and periodontitis are primarily infectious diseases caused by misplaced bacteria in the periodontal region. Without bacteria, the diseases disappear, although some of the sequelae such as bone loss become irreversible with disease progression. Accordingly, treatment of periodontitis is focused primarily on removal and elimination of the subgingival bacteria that cause disease. Physical removal by scaling and root planing is the standard therapeutic approach. Numerous clinical studies have demonstrated that antibiotic therapy as an adjunct to physical procedures is effective in halting and reversing disease progression, although the efficacy of antibiotics as sole treatment modality has not been carefully established. In general, prevention of periodontal disease, particularly at early stages, is not only important for overall health, but may also indirectly translate into lower total health care costs. Therefore, design and validation of novel non-surgical interventions and preventive strategies against periodontal disease is a major health care challenge. Given the primary bacterial infectious nature of the disease, improved antibiotics must play a central role in such efforts. Currently used antibiotics are mostly administered systemically, which can have serious side effects, particularly antibiotics- associated diarrhea, that preclude routine use for early stages of periodontal disease. The limited anatomic presence of bacteria in the periodontal region offers itself for topical antibiotic treatment, and antibiotic gels have been used with some success. However, the need for small volume administration, combined with limited potency and antimicrobial target specificity of available antibiotics, are likely to be limiting factors for achieving the full clinical potential of topical antibiotics in periodontitis. The overall goal of the proposed project is to develop a series of new antibiotics with markedly improved antimicrobial potency and selectivity against the major bacterial species associated with chronic periodontitis. Based on its proven efficacy in treating periodontitis, we will employ metronidazole as the lead compound to synthesize a structurally diverse library of nitro-heterocylic compounds by click chemistry approaches. Through comprehensive antimicrobial and acute toxicity testing, we anticipate to identify several promising antibiotics with improved activity against the most important periodontopathic bacteria in planktonic and biofilm conditions, and without acute toxicity in human cells. Such compounds, particularly when applied topically, have great potential to significantly advance the treatment options for periodontal diseases, and thereby help in achieving the ultimate goal of preventing unnecessary tooth mortality and aggravation of important systemic diseases in a large segment of the American public. Furthermore, timely and cost-effective intervention with more potent antibiotics, especially when used topically, has the potential to delay, and perhaps eliminate in some cases, the need for costly surgical therapies of periodontitis. Periodontal diseases, affecting a large segment of the American public, are primarily infectious diseases caused by misplaced bacteria in the periodontium. Physical removal of the responsible bacteria is the standard therapy, but antibiotics as adjuncts have clear beneficial effects. The project will develop new antibiotics with markedly improved antimicrobial potency and selectivity against the major bacterial species causing chronic periodontitis, which will help to significantly advance the treatment options and outcome for periodontal diseases.