Optimization and Lead Selection of Novel Antimycobacterial Agents

描述（由申请人提供）：随着机会性感染数量的增加，非结核分枝杆菌（NTM）是一个日益严重的公共卫生问题。虽然不是一种可报告的疾病，但越来越多的流行病学证据表明，在美国，NTM比结核分枝杆菌（Mtb）引起更多的感染，但与Mtb不同，很少有专门针对NTM的抗菌药物发现计划。由NTM引起的肺部疾病在具有潜在易感性的患者中尤其成问题，所述潜在易感性例如免疫抑制药物、囊性纤维化和其他肺部疾病、HIV和恶性肿瘤。鉴于NTM作为公共卫生问题的出现，寻找新的抗菌药物非常重要。我们已经筛选了具有抗NTM活性的新化合物库，重点是M。他发现了几个有希望的热门话题，这些话题围绕着三种化学上易于处理的小分子支架，它们表现出最小的细胞毒性。不同NTM的最小抑菌浓度（MIC）值范围为0.5至4 μ g/mL，因此为优化提供了相对有效的起点。重要的是，这些化合物中的每一种也具有抗结核杆菌的活性，使我们能够专注于广谱活性。我们建议进行药物化学命中铅优化，开发驱动抗菌活性的关键结构-活性关系的理解。在目标1中，我们将为三种支架中的每一种合成一小组类似物，重点是用于衍生化的有效位点，这将允许快速合成30-50种类似物。此外，在这些化合物系列中有76种市售类似物，便于快速组装至少100种类似物用于目标2中的测试。目标2的目标是根据生物学特性对支架进行优先级排序，首先对一组NTM（包括M）进行MIC测试。M.P. avium，M. intracellulare和M.龟类。显示出抗NTM活性的类似物将进展到针对Mtb和广泛的临床上重要的革兰氏阳性和革兰氏阴性病原体和真菌的二次筛选。进一步表征将包括分析人肝微粒体中的代谢稳定性、评估杀菌潜力、血清蛋白结合潜力和对外排抑制剂的敏感性。最有前途的脚手架就宽度而言， 抗菌谱、效力和药理学特性将被选择用于目标3中的深入药物化学优化，利用化学合成的迭代循环，然后进行生物特征分析，以指导SAR的开发。目标3的成功完成预计将产生一个或多个适合未来体内测试的复合电极导线。我们相信，这些化合物代表了一个令人兴奋的和有前途的起点，为发展一种新的治疗药物具有广泛的抗分枝杆菌活性。

DESCRIPTION (provided by applicant): The non-tuberculous mycobacteria (NTM) are a growing public health concern as the number of opportunistic infections increases. Although not a reportable disease, there is growing epidemiologic evidence to suggest that NTM cause more infections today in the United States than Mycobacterium tuberculosis (Mtb) yet, unlike Mtb, there are few dedicated antimicrobial drug discovery programs specifically for NTM. Pulmonary disease caused by NTM is especially problematic in patients with underlying susceptibilities such as immunosuppressive medications, cystic fibrosis and other lung diseases, HIV and malignancies. Given the emergence of NTM as a public health issue, finding new antibacterial agents is of high importance. We have screened libraries of novel compounds for anti-NTM activity, focusing on M. abscessus, and have found several promising hits centered around three chemically tractable small molecule scaffolds that exhibit minimal cytotoxicity. The minimum inhibitory concentrations (MIC) values range from 0.5 to 4 ¿g/mL for different NTM, thus providing a relatively potent starting point for optimization. Importantly, each of these compounds also has activity against Mtb, enabling us to focus on broad-spectrum activity. We propose to perform medicinal chemistry hit-to-lead optimization, developing an understanding of the key structure-activity relationships driving antibacterial activity. In Aim 1, we will synthesie a small set of analogs for each of three scaffolds, focusing on efficient sites for derivatization tht will allow for rapid synthesis of 30-50 analogs. In addition, there are 76 commercially available analogs within these compound series, facilitating rapid assembly of at least 100 analogs for testing in Aim 2. The goal of Aim 2 is to prioritize the scaffolds based on biological properties, beginning with MIC testing against a panel of NTM, including M. abscessus, M. avium, M. intracellulare, and M. chelonae. Analogs that show anti-NTM activity will progress to a secondary screen against Mtb and a broad panel of clinically important Gram-positive and Gram-negative pathogens and fungi. Further characterization will include analysis of metabolic stability in human liver microsomes, assessment of bactericidal potential, serum protein binding potential and sensitivity to efflux inhibitors. The most promising scaffold with respect to breadth of antimicrobial spectrum, potency and pharmacologic properties will be selected for in-depth medicinal chemistry optimization in Aim 3, utilizing an iterative cycle of chemical synthesis followed by biological profiling to guide the development of SAR. Successful completion of Aim 3 is expected to produce one or more compound leads suitable for future in vivo testing. We believe these compounds represent an exciting and promising starting point for the development of a novel therapeutic agent with broad antimycobacterial activity.