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: 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
• 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' 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，也被称为牙周病，是一种感染，可导致损害 以及牙齿周围牙龈和骨头的炎症。牙龈疾病的早期阶段是牙龈炎， 它由刷牙或用牙线清洁牙齿时出血的牙龈组成。如果不治疗， 牙周病，牙周炎，会导致牙齿松动甚至脱落。牙周炎与 一种叫做牙龈卟啉单胞菌的革兰氏阴性厌氧菌，它是一种关键的病原体， 这意味着牙龈卟啉单胞菌引起的损害与其丰度不成比例。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受影响， 甚至对目前使用的抗生素产生抗药性。因此，需要新型抗菌剂 选择性地对抗牙龈卟啉单胞菌来治疗牙周炎。最近，一个药物重新定位库的筛选 寻找抗菌化合物导致发现扎鲁司特（ZAF）作为先导化合物， 抗牙龈卟啉单胞菌活性。对于我的项目，我想开发具有抗牙龈卟啉单胞菌活性的ZAF衍生物。 为此，我提出了三个研究目标。一是合成新型ZAF衍生物 具有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、最小抑菌浓度、耐药性和 细胞毒性实验。如果发现所述化合物对哺乳动物细胞具有低毒性的有效性， 实验将提供对哪些官能团有益或有害于活性的深入了解。 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 在化学，生物化学和微生物学的技术技能，这项奖学金将允许发展 其他对我未来的行业职业生涯很重要的技能（例如，沟通（通过海报/口头介绍， 编写手稿和赠款申请）、建立联系、出席会议、发展 领导和指导技能等）。环境：肯塔基州大学的环境非常好。 有助于我准备一个成功的职业生涯中的工业与国家的最先进的设备，研讨会系列， 课程，研讨会，并有机会发展与校园内其他学院的合作。