Novel mycobacterial translocase I inhibitors--a new class of anti-TB drugs

描述（由申请人提供）：最近的统计数据将结核病列为全球每年造成近200万人死亡的严重传染病。世界上三分之一的人口感染了导致结核病的细菌病原体结核分枝杆菌（Mtb）。艾滋病毒/艾滋病增加了患结核病的风险，耐多药（MDR） Mtb菌株正在上升，威胁着世界人口。治疗结核病需要同时使用多种药物至少6个月。未能提供足够的药物或完成长期治疗导致耐多药Mtb的紧急情况。为了控制当前的结核病流行并最终根除该病，迫切需要能够缩短治疗活动性疾病并从无症状患者中消灭潜伏感染结核分枝杆菌的新型强效药物。自1997年成立以来，Sequella Inc.一直致力于开发包括新药在内的结核病新工具。以公司的使命为中心，本申请描述了开发一类新型结核分枝杆菌转座酶I抑制剂的研究计划，该抑制剂可阻断细菌细胞壁中肽聚糖的生物合成。目标是确定同类中最好的抑制剂，并完成将1个或更多的化合物推进临床前开发阶段所需的药理学表征。三共制药公司（Sankyo Pharma Inc.）最初发现和研究的3种候选化合物（1种为天然化合物）可抑制结核分枝杆菌在培养物和感染小鼠中的生长，具有低细胞毒性，对耐多药结核分枝杆菌有活性，并在肺部组织中具有高度分布。为了继续这些化合物的研发，我们计划评估它们在TB小鼠模型中的体内功效，重点是口服活性。我们将通过化学修饰探索天然化合物药效团的多样性。新的衍生物将通过一系列筛选进行筛选，以抑制转座酶I的活性，抑制培养中的结核分枝杆菌生长（MIC测定），使用MTS测定对人细胞的毒性，以及使用快速结核小鼠模型在体内的活性。从最初的3个和新的靶点中选出的最佳靶点将在慢性结核小鼠模型中进一步评估体内疗效，其中每种候选药物杀死或抑制结核分枝杆菌在感染动物的小鼠肺和脾脏中的复制的能力直接由菌落形成单位决定。这个I期建议将使我们能够选择最活跃的抗结核分枝杆菌转座酶I抑制剂，这些抑制剂可以推进到下一阶段的药物开发。

DESCRIPTION (provided by applicant): Recent statistics lists tuberculosis (TB) as a serious infectious disease that kills nearly 2 million people worldwide each year. 1/3rd of the world's population is infected with the bacterial pathogen, M. tuberculosis (Mtb) that causes TB. HIV/AIDs increases the risk of getting TB and multi-drug resistant (MDR) Mtb strains are on the rise, threatening the world population. Treatment of TB requires multiple drugs delivered concurrently for at least 6 months. Failure to provide adequate drugs or to complete the long term therapy results in emergency of MDR Mtb. In order to control the current TB epidemic and finally eradicate the disease, new potent drugs that can shorten the treatment active disease and eliminate latently infected Mtb from asymptomatic patients are desperately needed. Since its founding in 1997, Sequella Inc. has been contributing its entire R&D efforts in the development of new tools for TB, including new drugs. Centered on the company's mission, this application describes the research plans for the development of a novel class of Mtb translocase I inhibitors that block the biosynthesis of peptidoglycan in the bacterial cell wall. The goal is to identify the best inhibitors in the class and to complete the pharmacological characterization of the compounds required for advancing 1 or more into preclinical phase of the development. 3 candidates (1 is a natural compound) initially discovered and studied at Sankyo Pharma Inc. inhibit Mtb growth in cultures and in infected mice, have low cytotoxicity, are active against MDR-Mtb, and show high tissue distribution in lungs. To continue the R&D of these compounds, we plan to evaluate their in vivo efficacy in mouse models of TB emphasizing on oral activity. We will explore pharmacophore diversity of the natural compound by chemical modification. The new derivatives will be filtered throughout a series of screens for ability to inhibit translocase I activity, inhibition of Mtb growth in culture (MIC determination), toxicity in human cells using MTS assay, and in vivo activity using a rapid mouse model of TB. The top hits selected from the original 3 and the new hits will be evaluated further for in vivo efficacy in a chronic mouse model of TB, in which the ability of each drug candidate to kill or inhibit Mtb replication in mouse lung and spleen of infected animals is determined directly by colony-forming units. This phase I proposal will allow us to select the most active anti-Mtb translocase I inhibitors that can be advanced to the next phase of drug development.