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

基本信息

批准号：
10335152
负责人：
Kaitlind Howard
金额：
$ 3.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-22 至 2022-08-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335152
关键词：
Adhesions Alzheimer&apos 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

项目摘要

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，也称为牙周病，是一种可导致损害的感染以及牙齿周围的牙龈和骨骼发炎。牙龈疾病的早期阶段是牙龈炎，它由刷牙或使用牙线时牙龈出血组成。如果在晚期不及时治疗牙周病、牙周炎会导致牙齿松动甚至脱落。牙周炎有关联一种名为牙龈卟啉单胞菌的革兰氏阴性厌氧细菌，它是一种关键病原体，这意味着牙龈卟啉单胞菌造成的损害与其丰度不成正比。缺乏指导方针选择治疗牙周炎的抗生素方案导致细菌不易敏感对目前使用的抗生素产生耐药性，甚至产生耐药性。因此，需要新型抗菌剂选择性对抗牙龈卟啉单胞菌来治疗牙周炎。最近，筛选了一个药物重定位库寻找抗菌化合物导致了扎鲁司特 (ZAF) 作为先导化合物的发现针对牙龈卟啉单胞菌的活性。对于我的项目，我想开发具有对抗牙龈卟啉单胞菌活性的 ZAF 衍生物。为了做到这一点，我提出了三个研究目标。首先是合成新型ZAF衍生物具有对抗牙龈卟啉单胞菌的活性。第二个目标是确定这些衍生品的真正潜力：通过生长抑制百分比、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有效且毒性低，实验将深入了解哪些官能团对细胞的活性有益或有害化合物并允许进一步优化先导化合物。第三个目标是确定 ZAF 及其衍生物在牙龈卟啉单胞菌中的作用机制。培训计划：除了获得新的化学、生物化学和微生物学方面的技术技能，该奖学金将允许发展我未来在工业界的职业生涯的其他重要技能（例如，沟通（通过海报/口头演示和撰写手稿和资助申请）、建立人际网络、参加会议、发展领导能力和指导能力等）。环境：肯塔基大学的环境非常好通过最先进的设备、研讨会系列，有利于我为在工业界取得成功的职业生涯做好准备课程、研讨会以及与校园内其他学院开展合作的机会。