Target for Mefloquine in Mycobacteria

描述（由申请人提供）：分枝杆菌引起的感染是 导致严重的发病率和死亡率。结核分枝杆菌和 鸟分枝杆菌是细胞内的病原体，感染健康的 个体和免疫功能低下的患者。M.鸟类通常对 传统的抗结核治疗，并与少数药物显示， 抗M.在人类中的avium活性，如新的大环内酯类，治疗或 长期预防播散性疾病选择耐药突变体后， 单药治疗过程。此外，多重耐药病毒的多次爆发 M.结核病给医院和社区带来了临床挑战 病人的管理。本提案的目标是重点突出， 新的战略，以确定和特点的目标甲氟喹，一种药物 刚刚被确认对分枝杆菌有活性。我们发现 甲氟喹对两种M. avium和M.结核病和 对M.小鼠体内的鸟类微生物（我们没有 测试了体内抗M.肺结核）。因为甲氟喹可以 组织浓度达到血清浓度的80倍， 分枝杆菌在细胞内存活并且具有长的半衰期，这类分枝杆菌在细胞内存活并且具有长的半衰期。 化合物有可能成为抗分枝杆菌方案的一部分。 此外，甲氟喹对M.抗禽流感病毒株 大环内酯类，喹诺酮类，异烟肼，乙胺丁醇和利福平，提示一种新的 作用机制。因此，我们认为， 甲氟喹在分枝杆菌中的靶点可以为开发化合物开辟道路 甚至更强的活性。迄今为止用甲氟喹获得的结果 这表明它是第一个非常有效的抗分枝杆菌药物 好几年了具体而言，我们计划：（1）克隆甲氟喹 利用抗性突变体的抗性决定子。此外，通过使用M.鸟 启动子文库克隆在一个报告构建体（绿色荧光蛋白），我们 计划确定细菌中被抑制的途径， 当M. avium暴露于甲氟喹。这项工作，集中在一个 活性抗分枝杆菌化合物，具有揭示新靶点的潜力 在M. avium和M.结核

DESCRIPTION (provided by applicant): Infections caused by mycobacteria are responsible for severe morbidity and mortality. Mycobacterium tuberculosis and Mycobacterium avium are intracellular pathogens that infect both healthy individuals and immunocompromised patients. M. avium are usually resistant to conventional anti-tuberculosis therapy, and with the few drugs shown to have anti-M. avium activity in humans, such as the new macrolides, treatment or prolonged prophylaxis of disseminated disease selects resistant mutants after a course of monotherapy. In addition, multiple outbreaks of multi-drug resistant M. tuberculosis have created clinical challenges for hospital and community management of patients. The goal of this proposal is to be focused and apply new strategies to identify and characterize the targets of mefloquine, a drug just recognized to have activity against mycobacteria. We have found that mefloquine has in vitro activity against both M. avium and M. tuberculosis and is borderline bactericidal against M. avium organisms in mice (we have not tested the activity in vivo against M. tuberculosis). Because mefloquine can achieve tissue concentrations 80-fold greater than serum levels, and mycobacteria survive intracellularly and have a long half-life, this class of compound has potential to become part of anti-mycobacterial regimen. Furthermore, mefloquine is active against M. avium strain resistant to macrolides, quinolones, isoniazid, ethambutol and rifampin, suggesting a novel mechanism of action. Therefore, we believe that determining the biochemical target of mefloquine in mycobacteria can lead the way to developing compounds with even more potent activity. The results thus far obtained with mefloquine suggest that it is the first very active drug identified against mycobacteria in years. Specifically, we plan to: (1) clone the mefloquine resistant-determinant using resistant mutants. In addition, by using a M. avium promoter library cloned in a reporter construct (green fluorescent protein), we plan to determine the pathways in the bacterium that are inhibited or stimulated when M. avium is exposed to mefloquine. This work, focused on an active anti-mycobacterial compound, has the potential to unveil new target(s) in both M. avium and M. tuberculosis.