Macrocyclic proteasome inhibitors for treatment of tuberculosis

项目摘要/摘要 现有的治疗结核病的药物正在失去对耐药性的优势。有强烈的需求 开发包括抗结核分枝杆菌(Mtb)活性药物的新方案 处于缓慢或非复制状态的细胞(为简单起见，称为“NR”状态) 对大多数结核病药物的表型耐受性。我们的长期目标是开发抗结核分枝杆菌的药物 NR结核分枝杆菌种群以补充杀死复制的结核杆菌种群的药物。MTB依赖于 在宿主胁迫下生存的特定酶途径使其成为NR。其中包括 多年发现的原核泛素样蛋白(PUP)-蛋白酶体系统 从2003年开始。尽管在标准生长条件下，Mtb蛋白酶体是必不可少的。 在这种情况下，它已被证实为基因和药理学上的药物靶点： 敲除菌株在小鼠的慢性期死亡，我们介绍了几个 在体外杀死无压力或饥饿的结核分枝杆菌蛋白酶体抑制剂的类别。这些 包括对病原体的蛋白酶体选择性(&gt；1000倍)而不是对其 宿主，以及第一批通过抑制蛋白质分解而不是蛋白质来杀死细菌的药物 综合。到目前为止，抗生素的靶标只有五大类：抑制 核酸、蛋白质、细胞壁和叶酸的合成，以及膜的破坏。我们的 工作证实了第五类：抑制蛋白质降解途径，并导致了 其他人发现了能杀死原虫的病原体选择性蛋白酶体抑制剂 疟疾、恰加斯病和利什曼病。在这项申请中，我们将推进我们的新 发现了一类新的多肽类药物。我们证明了这些抑制剂是高度有效的 有效的和物种选择性的Mtb蛋白酶体抑制剂。我们建议进行领导 实现口服生物利用度和安全性的优化，用于未来的体内疗效研究 结核分枝杆菌感染小鼠模型。

Project Summary/Abstract Existing medicines for tuberculosis are losing ground to drug resistance. There is intense need to develop new regimens that include drugs active against Mycobacterium tuberculosis (Mtb) cells in the slowly- or non-replicating states (for simplicity, “NR” states) associated with phenotypic tolerance to most TB drugs. Our long-term goal is to develop anti-Mtb drugs that kill NR Mtb populations to complement drugs that kill replicating Mtb populations. Mtb relies on specific enzymatic pathways to survive the host stresses that make it NR. Among these is the prokaryotic ubiquitin-like protein (Pup)-proteasome system discovered over several years beginning in 2003. Although the Mtb proteasome is dispensable under standard growth conditions, it has been validated as a drug target both genetically and pharmacologically: the knock-out strain dies in the chronic phase of disease in mice, and we introduced several classes of Mtb proteasome inhibitors that kill NO-stressed or starved Mtb in vitro. These included the first inhibitors selective (>1000-fold) for the proteasome of a pathogen and not its host, and the first agents to kill bacteria by inhibiting protein breakdown rather than protein synthesis. Heretofore there have been only five broad classes of antibiotic targets: inhibition of synthesis of nucleic acids, proteins, cell walls and folate, and disruption of membranes. Our work has validated a fifth class: inhibition of a protein degradation pathway, and led to the discovery by others of pathogen-selective proteasome inhibitors that kill the protozoal agents of malaria, Chagas disease and Leishmaniasis. In this application, we will advance our newly discovered novel class of peptidomimetics. We demonstrate that these inhibitors are highly potent and species selective Mtb proteasome inhibitors. We propose to conduct lead optimization to achieve oral bioavailability with safety for future in vivo efficacy studies in mouse model of Mtb infection.