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。牙周病影响了很大一部分美国公众，超过50%的成年人患有牙龈炎，5-15%的人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，占美国牙齿死亡率的50-70%，并与包括糖尿病、心血管疾病和呼吸系统疾病在内的全身性疾病有关，并增加了早产低体重婴儿的风险。牙龈炎和牙周炎主要是由牙周区域错位的细菌引起的传染病。没有细菌，疾病就会消失，尽管随着疾病的进展，骨质流失等一些后遗症会变得不可逆转。因此，牙周炎的治疗主要集中在去除和消除引起疾病的牙龈下细菌。通过刮除和刨根的物理清除是标准的治疗方法。许多临床研究表明，作为物理治疗的辅助手段，抗生素治疗在阻止和逆转疾病进展方面是有效的，尽管抗生素作为唯一治疗方式的有效性尚未得到仔细证实。一般来说，牙周病的预防，特别是在早期阶段，不仅对整体健康很重要，而且还可能间接转化为降低总保健费用。因此，设计和验证针对牙周病的新型非手术干预和预防策略是一项主要的卫生保健挑战。鉴于这种疾病的主要细菌感染性，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，这可能会产生严重的副作用，特别是抗生素相关性腹泻，因此无法在牙周病的早期阶段常规使用。牙周区域细菌的有限解剖存在为局部抗生素治疗提供了条件，抗生素凝胶的使用取得了一些成功。然而，需要小容量给药，加上现有抗生素的效力和抗菌靶点特异性有限，可能是实现局部抗生素治疗牙周炎的全部临床潜力的限制因素。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着提高的抗菌效力和选择性。基于甲硝唑治疗牙周炎的疗效，我们将以甲硝唑为先导化合物，通过点击化学方法合成结构多样的硝基杂环化合物文库。通过全面的抗菌和急性毒性测试，我们期望找到几种有前景的抗生素，它们在浮游生物和生物膜条件下对最重要的牙周病细菌具有更好的活性，并且对人体细胞没有急性毒性。这种化合物，特别是局部应用时，具有极大的潜力，可以显著地促进牙周病的治疗选择，从而有助于实现在很大一部分美国公众中预防不必要的牙齿死亡和重要全身性疾病恶化的最终目标。此外，使用更有效的抗生素进行及时和具有成本效益的干预，特别是局部使用时，有可能延迟，甚至在某些情况下可能消除对牙周炎昂贵的手术治疗的需要。牙周病，影响了很大一部分美国公众，主要是由牙周组织错位的细菌引起的传染病。物理去除致病细菌是标准的治疗方法，但抗生素作为辅助手段具有明显的有益效果。该项目将开发具有显著提高抗菌效力和选择性的新型抗生素，以对抗引起慢性牙周炎的主要细菌种类，这将有助于显著推进牙周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.