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Siderophore-dependent inhibitors of Mycobacterium tuberculosis

结核分枝杆菌铁载体依赖性抑制剂

基本信息

批准号：
10199992
负责人：
MICHAEL NIEDERWEIS
金额：
$ 19.8万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-22 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199992
关键词：
Aerosols Affinity Biological Assay Blood Cells Cessation of life Communicable Diseases Complement Developing Countries Development Drug resistance Drug resistance in tuberculosis Environment Financial Hardship Genes Genetic Genome Granuloma Healthcare Systems Heme Histopathology Human In Vitro Infection Iron Kidney Lead Liver Lung Maximum Tolerated Dose Molecular Target Multidrug-Resistant Tuberculosis Mus Mutation Mycobacterium tuberculosis Patients Poisoning Predisposition Property Resistance Resistance development Role Siderophores Structure-Activity Relationship System Testing Time Toxic effect Tuberculosis Virulence bactericide base cost experimental study in vivo in vivo evaluation inhibitor/antagonist innovation mouse model mutant mycobactins nanomolar nephrotoxicity new therapeutic target novel pulmonary granuloma resistance frequency resistance mechanism screening small molecule synergism tuberculosis chemotherapy tuberculosis drugs uptake

项目摘要

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.

项目摘要 - 结核分枝杆菌铁载体依赖性抑制剂结核分枝杆菌 (Mtb) 是人类因传染病死亡的主要原因疾病。治疗感染耐药性的结核病患者的费用是天文数字 Mtb42 和很长的治疗时间给医疗保健系统带来了巨大的经济负担特别是在发展中国家。更具挑战性的是感染人数不断增加患有广泛或完全耐药的结核分枝杆菌，并且已经无法治疗。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。铁被获得结核分枝杆菌通过分泌铁载体，一种与铁具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对载铁铁载体的摄取。我们发现 Mtb 中铁载体分泌系统的基因失活导致细胞内铁载体的积累和结核分枝杆菌的自身中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测定以鉴定以铁载体依赖性方式抑制结核分枝杆菌的化合物。筛选 300,000 种化合物并进行后续构效关系 (SAR) 研究产生了四种具有令人兴奋特性的先导化合物（新的作用机制，纳摩尔具有抗结核分枝杆菌活性，毒性低，与某些结核病药物有较强的协同作用。这些初步的结果验证了铁载体分泌是 Mtb 的新型药物靶点。本次活动的目的建议在小鼠模型中检查铁载体依赖性抑制剂的活性结核病，以确定其抗耐药 Mtb 的活性并鉴定其分子目标。