Siderophore-dependent inhibitors of Mycobacterium tuberculosis

项目摘要-依赖铁载体的结核分枝杆菌抑制物 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天文数字 结核分枝杆菌42和非常长的治疗时间给#年的医疗保健系统带来了巨大的财政负担 特别是在发展中国家。更具挑战性的是感染人数的增加 患有广泛或完全耐药的结核分枝杆菌，已经变得无法治疗。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。铁是可以获得的 结核分枝杆菌通过分泌铁载体，对铁具有高亲和力的小分子，称为分枝杆菌蛋白 和羧基粘菌素以及随后铁载体的摄取。我们发现 结核分枝杆菌铁载体分泌系统的遗传失活导致细胞内 铁载体的蓄积和Mtb的自毒使其对小鼠的毒力降低更多 超过一万倍。基于这一观察，我们开发了一种创新的全细胞 筛选以铁载体依赖的方式抑制结核分枝杆菌的化合物。 300,000个化合物的筛选及其构效关系研究 合成了四种具有激发性质的先导化合物(新的作用机理，纳摩尔 对结核分枝杆菌有抗结核活性，毒性低，与一些结核病药物有很强的协同作用。这些初步的 结果证实铁载体分泌是结核分枝杆菌的一个新的可用药靶点。这样做的目的是 建议在小鼠模型中检查铁载体依赖的抑制物的活性 确定它们对耐药结核分枝杆菌的活性并鉴定它们的分子 目标。

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.