Novel gyrase inhibitors targeting Mycobacterium tuberculosis

针对结核分枝杆菌的新型旋转酶抑制剂

• 批准号: 10725711
• 负责人: Fenfei Leng
• 金额: $ 23.54万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-17 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725711
• 关键词: ATP phosphohydrolase; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Antitubercular Antibiotics; Bacterial DNA; Binding; Biochemical; Biological; Biological Assay; COVID-19 impact; COVID-19 pandemic; CRISPR interference; Cells; Cessation of life; Clinical; Communicable Diseases; Complex; DNA Damage; DNA Gyrase; Detection; Development; Drug Kinetics; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Enzymes; Evaluation; Fluorescence; Fluoroquinolones; Funding; Future; Grant; Growth; Human; In Vitro; Kinetics; Libraries; Mediating; Molecular; Molecular Bank; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Newly Diagnosed; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Poison; Poisoning; Property; Public Health; Reaction; Regimen; Reporting; Resistance; Series; Structure-Activity Relationship; Topoisomerase; Triage; Tuberculosis; Tuberculosis diagnosis; United States National Institutes of Health; World Health Organization; analog; cell killing; combat; cytotoxicity; design; drug metabolism; fluoroquinolone resistance; global health; high throughput screening; improved; in vivo; inhibitor; knock-down; molecular modeling; mutant; novel; pharmacologic; preclinical study; pyridine; quinolone resistance; repository; resistance mutation; side effect; small molecule libraries; success; targeted sequencing; therapeutically effective; transcriptome sequencing; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY This R21 project is designed to determine structure activity relationships (SARs) of a particular chemotype of 4-(1-methylimidazo[1,2-a]pyridine-1-ium (aka CPD229 and analogs), new antimycobacterial gyrase inhibitors discovered in our recent HTS campaign targeting bacterial DNA gyrase funded by an NIAID grant 1R21AI125973. We will also improve their Mycobacterium tuberculosis (Mtb) whole cell potency and pharmacological properties. Additionally, we will determine the mechanism of action (MoA) of these new gyrase inhibitors both in vitro using purified Mtb gyrase and in vivo within Mtb. DNA gyrase, an essential enzyme to Mtb, is an excellent and validated target for discovering and developing new antibiotics to treat MDR-TB. Fluoroquinolones (FQs), one of the most important and prescribed antibiotics, target bacterial DNA gyrase. FQs are widely used as anti-TB drugs, usually as the second-line antibiotics for MDR-TB patients. However, FQ-resistant Mtb strains have been discovered threatening the utility of FQ for TB treatment. Certain FQs also have serious side effects. These newly identified antimycobacterial gyrase inhibitors, structurally distinct from FQs, provide promising starting points for development and optimization of novel antibiotics that should yield effective therapeutics capable of overcoming FQ-resistance and effectively treating MDR-TB. Success in these proposed studies would provide potent non-FQ antimycobacterial gyrase inhibitors for the development of new antibiotics/therapy for the global public health problem of multi-drug resistant TB.

项目摘要 这个R21项目旨在确定特定化学型的结构活性关系（SAR）。 4-（1-甲基咪唑并[1，2-a]吡啶-1-鎓（又名CPD 229和类似物），新的抗分枝杆菌促旋酶抑制剂 在我们最近针对细菌DNA促旋酶的HTS运动中发现， 1R21AI125973。我们还将提高其结核分枝杆菌（Mtb）全细胞效力， 药理学特性此外，我们将确定这些新的作用机制（MoA）。 在体外使用纯化的Mtb促旋酶和在体内Mtb内的促旋酶抑制剂。DNA促旋酶，一种必需的 酶对结核分枝杆菌，是一个很好的和验证的目标，发现和开发新的抗生素，以治疗 耐多药结核病。氟喹诺酮类药物（Fluoroquinolones，FQs）是最重要的抗生素之一，以细菌DNA为靶点 旋转酶氟喹诺酮类抗生素是目前广泛使用的抗结核药物，通常作为耐多药结核病患者的二线抗生素。 然而，已经发现了耐药结核分枝杆菌菌株，威胁到FQ用于TB治疗的效用。某些 但也有严重的副作用。这些新鉴定的抗分枝杆菌促旋酶抑制剂， 与FQs不同，为开发和优化新型抗生素提供了有希望的起点， 应该产生能够克服耐药性和有效治疗耐多药结核病的有效治疗剂。 这些拟议研究的成功将为结核分枝杆菌提供有效的非FQ抗分枝杆菌促旋酶抑制剂。 为耐多药结核病这一全球公共卫生问题开发新的抗生素/疗法。