Discovery of novel agents against M. tuberculosis.

发现抗结核分枝杆菌的新型药物。

基本信息

批准号：
7912771
负责人：
Esteban Edward Mena
金额：
$ 30万
依托单位：
LIFEPHARMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7912771
关键词：
Agaricales American Antitubercular Agents Applications Grants Arts Ascomycota Basidiomycota Biological Biological Factors Candida albicans Cell Line Cells Cessation of life Chemicals Chicago Chromatography Development Directly Observed Therapy Drug resistance Escherichia coli Ethambutol Evaluation Exhibits Goals HIV High Pressure Liquid Chromatography Illinois Infection Institutes Lead Length Libraries Liquid substance Mammalian Cell Methods Mycobacterium tuberculosis Natural Product Drug Organism Pharmaceutical Preparations Poison Population Preparation Procedures Pyrazinamide Regimen Research Rifampin Sampling Screening procedure Selection Criteria Serum Source Speed Staphylococcus aureus Time Toxic effect Treatment Protocols Tuberculosis Universities cytotoxicity drug discovery drug metabolism global health high throughput screening in vitro Model in vivo isoniazid macrophage meetings novel pandemic disease phase 2 study public health relevance tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): Despite the fact that tuberculosis is a major public global health problem, there have been no drugs developed for it since the 1960s. In 2006 tuberculosis caused 1.7 million deaths annually with approximately 8 million new cases emerging annually. Tuberculosis has been exacerbated by human immunodeficiency virus pandemic with over 50% of deaths among the HIV-infected resulting from co- infection with Mycobacterium tuberculosis. The current treatment regimen of tuberculosis has been unchanged since the 1980s and relies on two months of intensive, directly observed therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol followed by a minimum of four months of isoniazid and rifampicin. One of the key reasons for the long length of a drug regimen is the subpopulation of isolates of M. tuberculosis that exhibit non-replicating persistence (NRP). Thus, screening for compounds against nonreplicating M. tuberculosis may lead to drugs that require a shorter drug regimen. Our goal is to identify novel drugs for the treatment of Tuberculosis. This grant proposal brings together the expertise the Institute for Tuberculosis Research at University of Illinois at Chicago (ITR- UIC), and LifePharms, a natural product drug discovery company. LifePharms possesses a unique and previously unprobed natural product library of prefractionated extracts of North American basidiomycetes and ascomycetes (mushrooms) and expertise in the isolation and structural identification of compounds from this source. We have now screened 29,000 fractions (out of a total of 200,000) and have identified 4 partially purified compounds with both potent activity against M. tuberculosis without being toxic to mammalian cells (selectivity > 10). More importantly, two of these compounds are also active against the nonreplicating persistence form of M. tuberculosis. Additionally, we have identified several other partially purified compounds with anti-tuberculosis activity. Here, we propose to a) evaluate all active fractions for activity vs mammalian cells and NPR-TB; b) determine activity against drug resistant TB and SNP cluster representatives with the compounds that meet our activity criteria, C) isolate and chemically identify the compounds with the best activity profile, and D) .Initiate the acquisition of larger amounts of the source organism or develop a synthesis plan for the most attractive compounds. PUBLIC HEALTH RELEVANCE: Despite the fact that tuberculosis is a major public global health problem, there have been no drugs developed for it since the 1960s. Moreover, tuberculosis has been exacerbated by human immunodeficiency virus pandemic with over 50% of deaths among the HIV-infected resulting from co-infection with Mycobacterium tuberculosis. We have discovered anti-TB lead compounds from an unexplored natural product. It is our goal to determine if these compounds represent new therapies for M. tuberculosis and develop them if warranted.

描述（由申请人提供）：尽管结核病是一个主要的全球健康问题，但自1960年代以来就没有开发过药物。 2006年，结核病每年造成170万人死亡，每年大约有800万例新病例。人类免疫缺陷病毒大流行使结核病加剧了，在与结核分枝杆菌共同感染引起的HIV感染者中，死亡人数超过50％。自1980年代以来，目前的结核病治疗方案一直保持不变，并依赖于两个月的密集，直接观察到的异念珠菌，利福平，吡嗪酰胺和乙糖醇的治疗，然后至少四个月的异oni氮氮杂和利福平。长长的药物方案的主要原因之一是表现出非复制持久性（NRP）的结核分枝杆菌分离株的亚群。因此，筛查对非复制的结核分枝杆菌的化合物可能导致需要较短的药物方案的药物。我们的目标是确定治疗结核病的新药物。该赠款提案汇集了伊利诺伊大学芝加哥大学（ITR-IIC）的结核病研究所的专业知识，以及天然产品药物发现公司Lifepharms。 Lifepharms拥有一个独特且以前未经探索的天然产品库，其中包括北美基本菌和子宫菌（蘑菇）的预分数提取物（蘑菇），并在该来源分离和结构鉴定化合物方面具有专业知识。现在，我们已经筛选了29,000个分数（在总计200,000个中），并鉴定了4种部分纯化的化合物，两种对结核分枝杆菌的有效活性而没有对哺乳动物细胞有毒（选择性> 10）。更重要的是，这些化合物中的两种也对结核分枝杆菌的非复制持续形式也有效。此外，我们已经确定了具有抗结核活性的其他几种部分纯化的化合物。在这里，我们建议a）评估所有活性分数与哺乳动物细胞和NPR-TB； b）确定具有符合我们活性标准的化合物，c）分离株并在化学上鉴定具有最佳活性曲线的化合物，并确定抗药性结核病和SNP簇代表的活性。公共卫生相关性：尽管结核病是全球主要的全球健康问题，但自1960年代以来就没有开发过药物。此外，人类免疫缺陷病毒大流行使结核病加剧了，与结核分枝杆菌共同感染引起的HIV感染的50％以上的死亡。我们已经从未开发的天然产品中发现了抗TB铅化合物。我们的目标是确定这些化合物是否代表结核分枝杆菌的新疗法，并在有必要的情况下开发它们。