Gyrase B Inhibitors for Mycobacterium Tuberculosis

结核分枝杆菌促旋酶 B 抑制剂

基本信息

批准号：
8534706
负责人：
PETER B MADRID
金额：
$ 18.7万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534706
关键词：
Active Sites Advanced Development Adverse effects Aerosols Affinity Americas Anti-Bacterial Agents Antibiotics Antitubercular Agents Area Aspartic Acid Binding Binding Sites Biochemical Biological Assay Biological Factors Cell Wall Cellular Assay Cessation of life Chemical Structure Chemicals Clinical Research Clinical Trials Colony-forming units Combined Modality Therapy Communicable Diseases Contracts DNA Gyrase Development Disease Drug Controls Drug Resistant Tuberculosis Drug resistance Drug-sensitive Fluorescence Polarization Goals Gram-Negative Bacteria Gram-Positive Bacteria Health Hazards Hydrogen Bonding Infection Knowledge Lead Length Libraries Methodology Molecular Weight Moxifloxacin Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Mycolic Acid Nature Patients Pharmaceutical Preparations Property Public Health Regimen Series Societies Thick Toxic effect Treatment Protocols Tuberculosis Vulnerable Populations Water Work bactericide base cheminformatics combinatorial compliance behavior design drug discovery effective therapy gyrB Protein high throughput screening improved in vitro activity in vivo inhibitor/antagonist isoniazid knowledge base next generation novel pathogen preclinical study public health relevance resistant strain scaffold screening tool treatment duration tuberculosis drugs tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for approximately 2 million deaths each year and remains a major public health hazard throughout the world. Existing treatments for both drug-sensitive TB and multi-drug resistant TB (MDR-TB) require prolonged treatment durations (6 months for drug-sensitive TB, 18-24 months for MDR-TB) and are difficult to administer. The inclusion of a fluoroquinoline antibiotic, which targets the A subunit of DNA gyrase (GyrA), into combination therapy regimens has improved culture conversion rates in clinical trials, indicating a potential to shorten treatment duration. Given the inevitable development of fluoroquinoline drug resistance, the B subunit of DNA gyrase (GyrB) is an attractive alternative target, with the potential to similarly shorten treatment length and perhaps also treat latent TB. The current classes of gyrase B inhibitors have only moderate anti-TB activity in vitro and in vivo, most likel due to their inability to efficiently penetrate the thick mycolic acid cell wall barrier of Mtb. Ths proposal will use a target-based screening strategy to rapidly identify new chemical scaffolds targeting GyrB with greater potential to be developed into anti-TB drugs. To accomplish this, structural information from existing high-affinity inhibitors and cheminformatics design principles will be used to design a GyrB-targeted combinatorial library to more efficiently explore the scaffold chemical space for this target. Parallel synthesis methodologies will be used to rapidly synthesize and purify this targeted library, which will then be screened for binding to gyrase B using a fluorescence polarization binding assay. New classes of inhibitors will then be profiled for microbiological activity and evaluated as new lead antitubercular compounds. This rational screening approach could potentially produce an important new class of antitubercular drugs with activity against MDR-TB and the ability to shorten treatment duration.

描述（由申请人提供）：结核分枝杆菌 (Mtb) 是结核病 (TB) 的病原体，每年导致约 200 万人死亡，并且仍然是全世界主要的公共卫生危害。药物敏感结核病和耐多药结核病 (MDR-TB) 的现有治疗方法需要较长的治疗时间（药物敏感结核病为 6 个月，耐多药结核病为 18-24 个月），并且难以实施。将靶向 DNA 旋转酶 (GyrA) A 亚基的氟喹啉抗生素纳入联合治疗方案中，可提高临床试验中的培养物转化率，表明有可能缩短治疗持续时间。鉴于氟喹啉耐药性不可避免的发展，DNA 旋转酶 (GyrB) 的 B 亚基是一个有吸引力的替代靶点，有可能同样缩短治疗时间，或许还可以治疗潜伏性结核病。当前类别的促旋酶 B 抑制剂在体外和体内仅具有中等抗结核活性，这很可能是由于它们无法有效穿透结核分枝杆菌厚的分枝菌酸细胞壁屏障。该提案将使用基于靶标的筛选策略来快速识别针对 GyrB 的新化学支架，这些支架具有开发成抗结核药物的更大潜力。为了实现这一目标，现有高亲和力抑制剂的结构信息和化学信息学设计原理将用于设计 GyrB 靶向组合库，以更有效地探索该靶标的支架化学空间。将使用平行合成方法快速合成和纯化该靶向文库，然后使用荧光偏振结合测定筛选其与旋转酶 B 的结合。然后将对新型抑制剂进行微生物活性分析，并作为新的主要抗结核化合物进行评估。这种合理的筛选方法可能会产生一类重要的新型抗结核药物，该药物具有抗耐多药结核病的活性，并且能够缩短治疗时间。