Mycobacterial Proteasome Inhibitors

结核分枝杆菌(结核分枝杆菌)已造成全球卫生紧急情况，并正在迅速恶化。 通过结核病大流行和抗生素大流行的交集 耐药性、艾滋病毒/艾滋病和肥胖相关的糖尿病。耐药结核病是一种 其低致病潜力被高潜在致病能力所抵消的生物恐怖主义威胁 扰乱经济。多药耐药(MDR)的治疗与广泛用药 耐药(XDR)结核病持续时间长、成本高、毒性大，死亡率高。然而，几乎没有 几十年来，针对结核分枝杆菌的新化疗已经出现。一种化疗的方法 由Dubos和Avery在1931年成功引入，但此后很少进行测试 以病原体中不是病原体在体外存活所必需的途径为靶点 但对病原菌抵抗寄主条件是必不可少的。MTB面临被动反应 氮中间体(RNI)、活性氧中间体(ROI)、酸、氨基酸 当它感染老鼠和人类时，缺乏和其他新陈代谢压力， 包括在潜伏性结核病感染(LTBI)期间。此应用程序基于标识 蛋白酶体作为结核分枝杆菌自我保护的非冗余途径 氧化/亚硝化应激和代谢的严格性。尽管蛋白酶体是 对于结核分枝杆菌在富含介质中的体外生长来说是必不可少的，它对于结核分枝杆菌在 老鼠，即使老鼠是免疫缺陷的。结核分枝杆菌蛋白酶体是可以下药的 作为一种重组蛋白复合体，在完整的Mtb内，以及临床批准的 蛋白酶体抑制剂Bortezomib(Velade“)在体外杀死结核分枝杆菌。这里我们将探索和 利用结核分枝杆菌蛋白酶体与人类蛋白酶体的差异来开发 具有足够的物种选择性、分枝杆菌摄取和对宿主无毒性的抑制剂 细胞作为新型抗结核化疗药物的先导。我们的前期工作 建议两个化合物类的成员可能符合这些标准：多肽 硼酸盐，包括VELCADE“，和恶硫唑-2-酮，一个新的 蛋白酶体生物学和药物化学。在这里开发的先导化合物可能 为结核病治疗提供两个新的化学类别，针对新的靶点，有效 对抗非复制型结核分枝杆菌，并可能对现有药物耐药的结核分枝杆菌起作用。 因为它们对非复制型结核分枝杆菌有效并且可能具有口服活性， 恶硫唑酮类药物可能有助于治疗目标人群中的LTBI，以减少 大流行。

M. tuberculosis (Mtb) has caused a global health emergency that is rapidly worsening through the intersection of the tuberculosis (TB) pandemic with epidemics of antibiotic resistance, HIV/AIDS and obesity associated diabetes. Drug-resistant TB is a bioterrorism threat whose low potential to cause disease is offset by a high potential to disrupt the economy. Treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB is prolonged, costly and toxic and the fatality rate is high. Yet little new chemotherapy against Mtb has emerged in decades. An approach to chemotherapy introduced successfully by Dubos and Avery in 1931 but rarely tested since then is to target a pathway in the pathogen that is not essential for the pathogen to survive in vitro but is essential for the pathogen to resist conditions in the host. Mtb faces reactive nitrogen intermediates (RNI), reactive oxygen intermediates (ROI), acid, amino acid deficiency and other metabolic stresses when it infects the mouse and perhaps man, including during latent TB infection (LTBI). This application is based upon identification of the proteasome as a non-redundant pathway by which Mtb protects itself against oxidative/nitrosative stress and metabolic stringency. Although the proteasome is dispensable for growth of Mtb in rich media in vitro, it is essential for Mtb to survive in mice, even when the mice are immunodeficient. The Mtb proteasome is druggable both as a recombinant protein complex and within intact Mtb, and a clinically approved proteasome inhibitor, bortezomib (Velcade"), kills Mtb in vitro. Here we will explore and exploit the differences between proteasomes from Mtb and humans so as to develop inhibitors with sufficient species selectivity, mycobacterial uptake and nontoxicity to host cells to serve as leads for novel anti-TB chemotherapeutics. Our preliminary work suggests that members of two compound classes may meet these criteria: peptidyl boronates, the class that includes Velcade", and oxathiazol-2-ones, a class new to proteasome biology and medicinal chemistry. Lead compounds developed here could offer two new chemical classes for TB therapeutics, directed to a new target, effective against non-replicating Mtb and presumably active on Mtb resistant to existing drugs. Because they are effective against non-replicating Mtb and are likely to be orally active, oxathiazolones might be useful to treat LTBI in targeted populations to curtail the pandemic.