Development of zafirlukast derivatives against Porphyromonas gingivalis

研究项目：牙周病，也被称为牙周病，是一种可导致损害的感染 牙齿周围的牙床和骨骼发炎。牙周病的早期阶段是牙周炎， 它由刷牙或用牙线清洁牙齿时会出血的牙床组成。如果不对其进行治疗， 牙周病，牙周炎，会导致牙齿松动甚至脱落。牙周炎与 一种名为牙龈卟啉单胞菌的革兰氏阴性厌氧细菌，这是一种关键的病原体， 这意味着牙龈假单胞菌造成的损害与其丰度不成正比。缺乏指导方针 因为选择一种抗生素方案来治疗牙周炎导致了较不敏感的细菌 对目前使用的抗生素产生抗药性或甚至抗药性。因此，需要新型抗菌剂。 有选择性地对抗牙周炎的牙周炎。近日，一个药物重新定位文库的筛选 寻找抗菌化合物导致了扎鲁司特(Zafirlukast)作为先导化合物的发现 对牙龈假单胞菌的活性。对于我的项目，我想开发ZAF衍生品，具有抗牙龈假单胞菌的活性。 为了做到这一点，我提出了三个研究目标。第一个是合成新型ZAF衍生物 具有抗牙龈假单胞菌的活性。第二个目标是确定这些衍生品的真实潜力 抗菌药物通过生长抑制率、最低抑菌浓度、耐药性和 细胞毒性实验。如果发现这些化合物对哺乳动物细胞具有低毒作用， 实验将提供对哪些官能团有益于或不利于 并允许进一步优化先导化合物。第三个目标是确定 ZAF及其衍生物在牙龈假单胞菌中的作用机制。培训计划：除了获得新的 在化学、生物化学和微生物学方面的技术技能，这一奖学金将允许发展 对于我未来的行业职业生涯来说，其他重要的技能(例如，沟通(通过海报/口头演示和 手稿和赠款申请的撰写)、联网、出席会议、制定 领导力和指导技能等)。环境：肯塔基大学的环境非常好 有助于为我在工业领域的成功职业生涯做好准备，拥有最先进的设备，研讨会系列， 课程、研讨会和与校园内其他学院发展合作的机会。

Research project: Gum disease, also known as periodontal disease, is an infection that can lead to damage and inflammation of the gum and bone that surround the teeth. The early stage of gum disease is gingivitis, which consists of gums that bleed when brushing or flossing teeth. When left untreated the late stage of periodontal disease, periodontitis, can lead to teeth that will loosen or even fall out. Periodontitis is associated with a Gram-negative anaerobic bacterium called Porphyromonas gingivalis, which is a keystone pathogen, meaning that the damage caused by P. gingivalis is not proportional to its abundance. The lack of guidelines for selecting an antibiotic regimen for the treatment of periodontitis has led to bacteria that are less susceptible to or even resistant to the antibiotics currently used. Therefore, there is a need for novel antibacterial agents to selectively combat P. gingivalis to treat periodontitis. Recently, a screening of a drug-repositioning library looking for antibacterial compounds led to the discovery of zafirlukast (ZAF) as a lead compound showing activity against P. gingivalis. For my project I want to develop ZAF derivatives with activity against P. gingivalis. In order to do this, I have come up with three research aims. The first is to synthesize novel ZAF derivatives with activity against P. gingivalis. The second aim is to determine the true potential of these derivatives as antibacterial agents through percent growth inhibition, minimum inhibitory concentration, resistance, and cytotoxicity experiments. If the compounds are found to be potent with low toxicity to mammalian cells, the experiments will provide insight into which functional groups are beneficial or detrimental to the activity of the compounds and allow for further optimization of lead compounds. The third aim is to determine the mechanism of action of ZAF and its derivatives in P. gingivalis. Training plan: In addition to gaining new technical skills in chemistry, biochemistry, and microbiology, this Fellowship will allow for development of other important skills for my future career in industry (e.g., communication (via poster/oral presentations and writing of manuscripts and grant applications), networking, attendance at conferences, development of leadership and mentoring skills, etc). Environment: The environment at the University of Kentucky is highly conducive to preparing me for a successful career in industry with state-of-the-art equipment, seminar series, courses, workshops, and opportunities to develop collaborations with other Colleges on campus.