High throughput TB drug screens

高通量结核病药物筛选

• 批准号: 6653780
• 负责人: Carol A. Nacy
• 金额: $ 17.28万
• 依托单位: SEQUELLA GLOBAL TUBERCULOSIS FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653780
• 关键词: Mycobacterium tuberculosis; antitubercular agents; bacterial genetics; biotechnology; combinatorial chemistry; drug screening /evaluation; ethambutol; genetic techniques; high throughput technology; microorganism culture

DESCRIPTION (adapted from applicant's abstract): The search for new TB drugs has finally caught up with the pharmaceutical revolution of the last half of this century: solid-matrix-based methods of chemical synthesis now create combinatorial chemistry libraries of pharmaceuticals that contain millions of unique compounds. Using robotics and sophisticated assay instrumentation, these libraries can be screened with high throughput to identify compounds which are lethal to specific organisms, or which affect specific pathways know to be critical for bacterial survival. A year-old CRADA between the NIAID and Sequella, Inc. to develop combinatorial chemistry and a high throughput screening assay succeeded in synthesizing and screening approximately 100,000 analogues of the TB drug ethambutol in a very short period of time. The gene- based screen used in these studies identified compounds that affect specific regions of the M. tuberculosis genome that are activated in response to ethambutol therapy, and are involved in the cellular response to cell wall damage. The Sequella, Inc./NIH collaboration had impressive momentum (100,000 compounds screened, 200 hits, 4 lead compounds in 9 months). The Foundation intends to provide several gene-based and whole-cell high throughput screening assays to interested pharmaceutical companies to screen their chemical libraries in a similar timeframe. One company, for example, has 500,000 well- characterized chemicals taht have never been tested for TB. They are interested in providing the Foundation with these chemicals to test in a specific whole cell-screening assay as an initial screen for hits. Setting up the high throughput screen in-house, while not that expensive, represents an opportunity cost for that company and would require a BL3 facility. In addition, a validated whole-bacteria high throughput screening assay would be of benefit to the current NIAID/DAIDS drug screening program. The Foundation would be interested in transferring the screen to the NIH program over the course of this challenge grant. The Foundation goal is to reduce the barriers to entry that the major pharmaceutical companies face when considering the market for new TB drugs. Thus, providing tailored screening programs that support the specific needs of pharmaceutical partners is a relatively inexpensive endeavor that may improve the likelihood that medicines will emerge to improve the treatment of this neglected disease.

描述（改编自申请人摘要）：寻找新的结核病药物 终于赶上了20世纪后半叶的制药革命 本世纪：基于固体基质的化学合成方法现在创造了 药物的组合化学库， 独特的化合物 使用机器人技术和复杂的分析仪器， 可以高通量筛选这些文库以鉴定化合物 对特定的生物体是致命的，或者影响特定的途径， 对细菌的生存至关重要。 一年的CRADA之间的NIAID和 Sequella，Inc.发展组合化学和高通量 筛选试验成功地合成和筛选了大约10万个 结核病药物乙胺丁醇的类似物在很短的时间内。 基因- 这些研究中使用的基于筛选的方法鉴定了影响特定 M.结核病基因组中， 乙胺丁醇治疗，并参与细胞对细胞壁的反应 损害 The Sequella，Inc. NIH的合作势头令人印象深刻（10万 筛选化合物，200次点击，9个月内筛选出4种先导化合物）。 了基础 旨在提供几种基于基因和全细胞的高通量筛选 分析，以感兴趣的制药公司筛选他们的化学品 图书馆在类似的时间。 例如，一家公司拥有50万名员工- 从未被测试过结核病的化学物质。 他们是 有兴趣为基金会提供这些化学品， 特异性全细胞筛选测定作为命中的初始筛选。 建立 内部高通量筛选，虽然不是那么昂贵， 该公司的机会成本，并需要BL 3设施。 此外，经验证的全细菌高通量筛选测定将 对目前的NIAID/DAIDS药物筛查计划有益。 的 基金会将有兴趣将屏幕转移到国家卫生研究院计划 在这个挑战奖的过程中。 基金会的目标是减少进入的障碍， 制药公司在考虑新结核病药物市场时面临的问题。 因此，提供量身定制的筛选方案，支持特定的需求， 制药合作伙伴是一个相对便宜的奋进，可以改善 药物出现的可能性，以改善这种治疗， 被忽视的疾病