High throughput TB drug screens

高通量结核病药物筛选

• 批准号: 6534323
• 负责人: Carol A. Nacy
• 金额: $ 15.7万
• 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/6534323
• 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（改编自申请人的摘要）：寻找新的结核病药物终于赶上了后半部分的药物革命 本世纪：基于固体基质的化学合成方法 药品的组合化学库，其中包含数百万美元 独特的化合物。 使用机器人技术和复杂的测定仪器， 这些库可以用高吞吐量筛选以识别化合物 对特定生物的致命性或影响特定途径的人知道 对于细菌生存至关重要。 Niaid和 Sequella，Inc。开发组合化学和高通量 筛选测定成功合成和筛选约100,000 在很短的时间内，结核病药物的类似物。 基因 - 这些研究中使用的基于屏幕确定了影响特定的化合物 结核分枝杆菌基因组的区域被激活 乙酰丁醇治疗，并参与细胞对细胞壁的反应 损害。 Sequella，Inc./nih合作具有令人印象深刻的动力（100,000 筛选的化合物在9个月内进行了200次命中，4种铅化合物）。 基础 打算提供几种基于基因的和全细胞高吞吐量筛选 向感兴趣的制药公司进行测定以筛选其化学品 在类似的时间范围内的库。 例如，一家公司拥有500,000个井 特征化学物质TAHT从未对结核病进行测试。 他们是 有兴趣为基础提供这些化学物质以在 特定的全细胞筛分测定作为命中的初始屏幕。 设置 内部高吞吐量屏幕虽然不太昂贵，但代表 该公司的机会成本，需要BL3设施。 此外，经过验证的全部细菌高通量筛选测定法会 对当前的NIAID/DAIDS药物筛查计划有益。 这 基金会有兴趣将屏幕转移到NIH计划 在这项挑战赠款的过程中。 基础目标是减少进入障碍 在考虑新的结核病药物市场时，制药公司面临。 因此，提供量身定制的筛选程序，以支持 药品合作伙伴是一项相对便宜的努力，可以改善 药物会出现改善治疗的可能性 被忽视的疾病。