Development of zafirlukast derivatives against Porphyromonas gingivalis

抗牙龈卟啉单胞菌的扎鲁司特衍生物的开发

• 批准号: 10224464
• 负责人: Kaitlind Howard
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-22 至 2024-01-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224464
• 关键词: Adhesions; Alzheimer' s Disease; Amoxicillin; Anaerobic Bacteria; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Applications Grants; Bacteria; Biochemistry; Biological; Cardiovascular Diseases; Cells; Chemicals; Chemistry; Collaborations; Communication; Development; Diabetes Mellitus; Disease; Disease Progression; Doxycycline; Drug Design; Drug Targeting; Drug resistance; Educational workshop; Environment; Epithelial Cells; Equipment; Evaluation; FDA approved; Feedback; Fellowship; Future; Generations; Gingiva; Gingivitis; Goals; Gram-Negative Anaerobic Bacteria; Gram-Positive Bacteria; Growth; Guidelines; Human; Hydrogen Peroxide; Industry; Infection; Inflammation; Kentucky; Lead; Left; Libraries; Mammalian Cell; Manuscripts; Mental disorders; Mentors; Metronidazole; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration measurement; Modification; Oral; Parents; Pathogenicity; Peptide Hydrolases; Periodontal Diseases; Periodontitis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Porphyromonas gingivalis; Property; Public Health; Regimen; Research; Research Project Grants; Resistance; Resistance development; Rheumatoid Arthritis; Series; Streptococcus sanguis; Structure; Structure-Activity Relationship; Technical Expertise; Tissues; Tooth structure; Toxic effect; Training; Treatment Protocols; Universities; Virulence Factors; Writing; bacterial resistance; bone; career; college; combat; commensal bacteria; cytotoxic; cytotoxicity; drug candidate; drug development; drug resistant bacteria; dysbiosis; experimental study; falls; functional group; gingipain; insight; lead optimization; leadership development; metal chelator; mutant; novel; novel therapeutics; oral biofilm; oral cavity epithelium; pathogen; pathogenic bacteria; polymicrobial biofilm; posters; screening; skills; symposium

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.

研究项目：牙龈疾病，也称为牙周疾病，是一种可能导致损害的感染 以及围绕牙齿的口香糖和骨骼的炎症。牙龈疾病的早期阶段是牙龈炎， 由牙齿或牙线牙齿流血的牙龈组成。当不加以治疗的后期 牙周疾病，牙周炎可能会导致牙齿会松动甚至会掉落。牙周炎是相关的 革兰氏阴性厌氧菌称为牙龈卟啉单胞菌，这是一种基石病原体， 这意味着牙龈疟原虫造成的损害与其丰度成正比。缺乏准则 用于选择用于牙周炎治疗的抗生素方案导致细菌易感性 对当前使用的抗生素具有抗性。因此，需要新颖的抗菌剂 有选择地对抗牙龈疟原虫来治疗牙周炎。最近，筛选毒品文库 寻找抗菌化合物导致Zafirlukast（ZAF）作为铅化合物的发现 针对牙龈疟原虫的活性。对于我的项目，我想开发具有针对牙龈疟原虫的活动的ZAF衍生物。 为此，我提出了三个研究目标。首先是合成新颖的ZAF衍生物 具有针对牙龈疟原虫的活性。第二个目的是确定这些衍生物的真正潜力 通过抑制百分比，最小抑制浓度，耐药性和 细胞毒性实验。如果发现化合物对哺乳动物细胞的毒性低，则 实验将提供深入了解哪些官能团对活动的有益或有害 化合物并允许进一步优化铅化合物。第三个目的是确定 ZAF及其衍生物在牙龈疟原虫中的作用机理。培训计划：除了获得新 化学，生物化学和微生物学方面的技术技能，该研究金将允许发展 我未来行业职业的其他重要技能（例如，沟通（通过海报/口头演示和 撰写手稿和赠款申请），网络，出席会议，发展 领导力和指导技能等）。环境：肯塔基大学的环境很高 有利于我为我的最先进的设备，研讨会系列的工业事业做好准备， 课程，讲习班以及与校园其他大学合作的机会。