Siderophore-dependent inhibitors of Mycobacterium tuberculosis

项目概要-结核分枝杆菌铁载体依赖抑制剂 结核分枝杆菌（Mtb）是人类死于传染性疾病的主要原因。 疾病治疗耐药结核病患者的巨额费用 结核病42和非常长的治疗时间对卫生保健系统造成了巨大的财政负担， 特别是在发展中国家。更具挑战性的是， 广泛或完全耐药的结核病已经无法治愈。因此 迫切需要开发新的结核病药物，最好是针对新的药物靶点的药物。铁是获得 结核分枝杆菌通过分泌铁载体，对铁有高亲和力的小分子称为分枝杆菌素 和羧基分枝杆菌素以及随后的铁载体的摄取。我们发现 Mtb中铁载体分泌系统的遗传失活导致细胞内 铁载体的积累和Mtb的自我中毒进一步降低了其在小鼠中的毒力 超过一万倍。基于这一观察，我们开发了一种创新的全细胞 筛选试验以鉴定以铁载体依赖性方式抑制Mtb的化合物。 筛选约300，000种化合物并进行后续的构效关系（SAR）研究 产生了四个具有令人兴奋的性质的先导化合物（新的作用机制，纳摩尔 抗结核活性高，毒性低，与某些结核病药物有很强的协同作用。这些初步 结果证实了铁载体分泌作为Mtb的新的和可药物化的靶点。其目的是 建议是在小鼠模型中检查铁载体依赖性抑制剂的活性， 结核病，以确定其对耐药Mtb的活性，并确定其分子 目标的

Project Summary - Siderophore-dependent inhibitors of Mycobacterium tuberculosis Mycobacterium tuberculosis (Mtb) is the leading cause of human deaths from an infectious disease. The astronomical costs of treating tuberculosis patients infected with drug-resistant Mtb42and the very long treatment times pose a huge financial burden on health care systems in particular in developing countries. Even more challenging is the increasing number of infections with extensively or totally drug-resistant Mtb that have become untreatable. Thus, the development of new TB drugs, preferably against new drug targets, is urgent. Iron is acquired by Mtb by secreting siderophores, small molecules with high affinity for iron called mycobactins and carboxymycobactins and subsequent uptake of iron-loaded siderophores. We discovered that genetic inactivation of the siderophore secretion system in Mtb leads to intracellular accumulation of siderophores and self-poisoning of Mtb reducing its virulence in mice by more than 10,000-fold. Based on this observation we have developed an innovative, whole-cell screening assay to identify compounds which inhibit Mtb in a siderophore-dependent manner. Screening of 300,000 compounds and subsequent structure-activity relationship (SAR) studies yielded four lead compounds with exciting properties (novel mechanism of action, nanomolar activities against Mtb, low toxicity and strong synergy with some TB drugs. These preliminary results validated siderophore secretion as a novel and druggable target of Mtb. The aims of this proposal are to examine the activity of siderophore-dependent inhibitors in a mouse model of tuberculosis, to determine their activity against drug-resistant Mtb and to identify their molecular targets.