Mycobacterial Proteasome Inhibitors

M.结核病（Mtb）已造成全球卫生紧急情况，并正在迅速恶化 通过结核病大流行与抗生素流行的交叉， 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 生物恐怖主义威胁，其导致疾病的低潜力被高潜力所抵消， 扰乱经济。多药耐药（MDR）和广泛耐药的治疗 耐药（XDR）结核病是长期的、昂贵的和有毒的，并且死亡率很高。甚少 几十年来出现了针对结核分枝杆菌的新的化学疗法。化疗的方法 由Dubos和Avery于1931年成功引入，但此后很少进行测试， 靶向病原体中对病原体在体外存活不是必需的途径 但对于病原体抵抗宿主的条件是必需的。结核分枝杆菌面临反应性 氮中间体（RNI）、活性氧中间体（ROI）、酸、氨基酸 缺乏和其他代谢压力，当它感染小鼠，也许人， 包括在潜伏性TB感染（LTBI）期间。这项申请是基于识别 蛋白酶体作为Mtb保护自身免受 氧化/亚硝化应激和代谢严格性。虽然蛋白酶体是 对于结核分枝杆菌在富培养基中的体外生长，结核分枝杆菌在富培养基中存活是必需的。 小鼠，即使小鼠是免疫缺陷的。结核分枝杆菌蛋白酶体是可药用的， 作为重组蛋白复合物并在完整的Mtb内，以及临床上批准的 蛋白酶体抑制剂硼替佐米（Velcade）在体外杀死Mtb。在这里，我们将探索和 利用结核分枝杆菌和人类蛋白酶体之间的差异， 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 细胞作为新的抗结核化疗药物的先导。我们的前期工作 表明两种化合物类别的成员可能符合这些标准： 硼酸酯，包括Velcade”的类别，和恶唑-2-酮， 蛋白酶体生物学和药物化学。这里开发的铅化合物可以 为结核病治疗提供了两种新的化学类别，针对新的靶点，有效 抗非复制型结核分枝杆菌，并可能对耐现有药物的结核分枝杆菌有活性。 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， 氧噻唑酮可能有助于治疗目标人群中的LTBI， 流行病

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.