Dual Targeting of Mtb Resistance Mechanisms

结核病耐药机制的双重靶向

• 批准号: 10686882
• 负责人: Christoph Grundner
• 金额: $ 79.69万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686882
• 关键词: Acceleration; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Area; Bacteria; Biological Availability; Cause of Death; Cessation of life; Chemicals; Clinical; Combined Antibiotics; Communicable Diseases; Confocal Microscopy; Data; Drug Kinetics; Drug Targeting; Drug Tolerance; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Extreme drug resistant tuberculosis; Flow Cytometry; Genetic; Growth Factor Receptors; Human; Immune; Immune response; Immunity; Immunologic Factors; Impairment; Infection; Inflammation; Integration Host Factors; Interferon Type II; Lung; Macrophage; Mediating; Molecular; Molecular Target; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Oral; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population; Proteomics; Receptor Inhibition; Receptor Signaling; Recommendation; Resistance; Rifampin; Role; Series; Side; Signal Transduction; Site; T cell response; T-Lymphocyte; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Tuberculosis; Validation; analog; cell type; cellular targeting; drug efficacy; efficacy testing; emerging antibiotic resistance; genetic approach; genome sequencing; improved; in vitro activity; in vivo; in vivo evaluation; inhibitor; mouse model; mutant; novel; novel therapeutics; pathogen; prevent; resistance mechanism; resistant strain; targeted treatment; therapy duration; tool; tuberculosis drugs; tuberculosis immunity; tuberculosis treatment

ABSTRACT Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, currently leads to nearly 1.7 million deaths a year. TB control is threatened by the continued emergence of drug-resistant Mtb strains. Clinical resistance has now been observed against all TB drugs, underscoring the urgent need not just for new drugs, but for entirely new strategies that directly target and disable drug resistance mechanisms. Two of the most promising strategies to prevent the emergence of antibiotic resistance in the treatment of TB are the targeting of drug tolerant, non-replicating bacterial populations and host-directed therapy (HDT). We identified a series of drug-like ATP analogs with in vitro activity against replicating and non-replicating Mtb that is comparable to that of rifampicin, one of the first-line drugs targeting non-replicating Mtb. Because these inhibitors were originally developed for the inhibition of the human transforming growth factor receptor (TGFβR), a pathway implicated in immunity to TB, we also sought to test whether inhibition of TGFβR mediates host-directed activity against Mtb. We found that genetic deletion and chemical inhibition of TGFβR significantly reduced the bacterial load in infected animals. We showed that T-cells lacking TGFβR had an increased capacity to interact in a cognate manner with Mtb-infected macrophages and produce IFNγ at the pulmonary site of infection. These preliminary studies suggest a new answer to the longstanding question why the T cell response to Mtb is inadequate at the site of infection and highlights the possibility that TGFβ signaling is a new HDT target. Thus, we identified compounds that have two independent activities that both kill Mtb and likely impede the emergence of drug resistance. Using genetics and the ATP analogs as chemical tools, we will identify the cellular Mtb targets responsible for directly killing Mtb, thus identifying new targets that underlie drug tolerance. On the host side, we will determine the role of TGFβR signaling in Mtb infection. Lastly, we will test this dual host-pathogen targeting strategy by testing the efficacy of our compounds in vivo.

抽象的 结核分枝杆菌（MTB），人类结核病（TB）的病因，目前几乎导致 每年170万人死亡。 TB控制受到抗药性MTB菌株的持续出现的威胁。 现在已经观察到针对所有结核病药物的临床抵抗力，不仅强调了紧急的需求 药物，但针对直接针对和禁用耐药机制的全新策略。两个 防止结核病治疗中抗生素耐药性出现的最有希望的策略是 靶向药物耐药，非复制细菌群体和宿主定向治疗（HDT）。我们确定了一个 具有体外活性的一系列类似药物样的ATP类似物，反对复制和非复制MTB 对于利福平，这是针对非复制MTB的一线药物之一。因为这些抑制剂是 最初是为抑制人转化生长因子受体（TGFβR）而开发的，这是一种途径 以对TB的免疫力实施，我们还暗示测试TGFβR的抑制是否介导了宿主指导的活性 反对MTB。我们发现遗传缺失和TGFβR的化学抑制可显着降低细菌 在感染动物中负载。我们表明缺乏TGFβR的T细胞具有增加在A中相互作用的能力 用MTB感染的巨噬细胞进行认知方式，并在感染的肺部产生IFNγ。这些 初步研究提出了一个长期以来的问题的新答案，为什么T细胞对MTB的反应是 在感染部位不足，突出了TGFβ信号传导是一个新的HDT靶标的可能性。那， 我们确定了具有两种独立活动的化合物，既杀死MTB又可能阻碍出现 耐药性。使用遗传学和ATP类似物作为化学工具，我们将确定细胞MTB靶标 负责直接杀死MTB，从而确定了具有药物耐受性的新目标。在主机方面，我们 将确定TGFβR信号在MTB感染中的作用。最后，我们将测试这个双重宿主靶向靶向 通过在体内测试我们化合物的效率来策略。