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：
8364850
负责人：
PETER B MADRID
金额：
$ 23.19万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8364850
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 Screening procedure 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 resistant strain scaffold 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. PUBLIC HEALTH RELEVANCE: The goal of the project is to create improved treatment regimens for drug-resistant tuberculosis infections that will be of shorter duration and have fewer side effects. The development of a shorter, more effective treatment regimen will increase patient compliance and thereby slow down the emergence of drug resistance and protect vulnerable populations worldwide.

描述（由申请人提供）：结核分枝杆菌（MTB），结核病的病因（TB），每年造成约200万人死亡，并且仍然是全世界的主要公共卫生危害。药物敏感性结核病和多药耐药结核病（MDR-TB）的现有治疗需要延长治疗持续时间（药物敏感的结核病为6个月，MDR-TB为18-24个月），并且难以给药。将氟喹啉抗生素靶向DNA回旋酶（Gyra）的A亚基中，在临床试验中，将DNA Gyrase（Gyra）亚基靶向组合治疗方案，可以提高培养率，这表明有可能缩短治疗持续时间。鉴于不可避免的氟喹啉耐药性的发展，DNA回旋酶（Gyrb）的B亚基是一个有吸引力的替代靶标，具有类似缩短治疗长度的潜力，也许也可以治疗潜在的TB。当前的回旋酶B抑制剂在体外和体内仅具有中等的抗TB活性，由于它们无法有效地穿透MTB的厚霉菌酸细胞壁屏障，因此大多数可能会产生。 THS提案将使用基于目标的筛查策略来快速识别针对Gyrb的新化学支架，其潜力更大，可以发展为抗TB药物。为此，来自现有的高亲和力抑制剂和化学信息设计原理的结构信息将用于设计一个针对GYRB的组合库，以更有效地探索该目标的脚手架化学空间。平行合成方法将用于快速合成和纯化该靶向文库，然后使用荧光极化结合测定法对其进行筛选以与Gyrase B结合。然后，将针对微生物活性进行新的抑制剂类别，并评估为新的铅抗结核化合物。这种合理的筛查方法可能会产生重要的新一类抗结核药物，具有针对MDR-TB的活性以及缩短治疗持续时间的能力。公共卫生相关性：该项目的目的是为耐药性结核病感染创造改进的治疗方案，该治疗持续时间较短，副作用较少。较短，更有效的治疗方案的发展将提高患者的依从性，从而减缓耐药性的出现并保护全球脆弱的人群。