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.