Discovery of novel agents against M. tuberculosis.

发现抗结核分枝杆菌的新型药物。

• 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
• 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

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(申请人提供)：尽管结核病是一个主要的全球公共卫生问题，但自20世纪60年代以来一直没有针对它的药物开发。2006年，结核病每年造成170万人死亡，每年新增约800万例。人类免疫缺陷病毒大流行加剧了结核病，艾滋病毒感染者中有50%以上的死亡是由结核分枝杆菌混合感染造成的。目前的结核病治疗方案自1980年代以来一直没有改变，依赖于两个月的强化、直接观察的异烟肼、利福平、吡津酰胺和乙胺丁醇治疗，然后至少四个月的异烟肼和利福平治疗。一种药物方案持续时间长的关键原因之一是表现出非复制性持久性(NRP)的结核分枝杆菌分离株的亚群。因此，筛选抗非复制型结核分枝杆菌的化合物可能会导致需要较短用药方案的药物。我们的目标是寻找治疗结核病的新药。这项拨款提案汇集了伊利诺伊大学芝加哥分校结核病研究所(ITR-UIC)和天然产物药物发现公司LifePharms的专业知识。LifePharms拥有北美担子菌和子囊菌(蘑菇)预分提物的独特天然产品库，以及从这一来源分离和结构鉴定化合物的专业知识。我们现在已经筛选了29,000个组分(总共200,000个组分)，并鉴定了4个部分纯化的化合物，它们既有强大的抗结核活性，又对哺乳动物细胞没有毒性(选择性&gt；10)。更重要的是，其中两种化合物对非复制型持久性结核分枝杆菌也有活性。此外，我们还鉴定了其他几个部分纯化的具有抗结核活性的化合物。在这里，我们建议a)评估所有活性部分对哺乳动物细胞和NPR-TB的活性；b)用符合我们活性标准的化合物来确定抗耐药TB和SNP簇的活性；C)分离和化学鉴定活性最好的化合物；以及D)开始获取更多的来源生物体或为最有吸引力的化合物制定合成计划。 与公共卫生相关：尽管结核病是一个重大的全球公共卫生问题，但自20世纪60年代以来一直没有针对它的药物开发。此外，人类免疫缺陷病毒大流行加剧了结核病，艾滋病毒感染者中有50%以上的死亡是由结核分枝杆菌混合感染造成的。我们从一种未开发的天然产品中发现了抗结核病的先导化合物。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，并在必要时开发它们。