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) 是人类结核病 (TB) 的病原体，目前导致几乎 每年有 170 万人死亡，结核病控制受到耐药结核菌菌株持续出现的威胁。 目前已观察到所有结核病药物均出现临床耐药性，这凸显出迫切需要的不仅仅是新药 药物，而是直接针对和禁用其中两种耐药机制的全新策略。 预防结核病治疗中抗生素耐药性出现的最有希望的策略是 我们确定了针对耐药、非复制细菌群体和宿主定向治疗（HDT）的方法。 系列药物样 ATP 类似物，其体外对抗复制型和非复制型 Mtb 的活性相当 利福平是针对非复制型结核分枝杆菌的一线药物之一，因为这些抑制剂是针对非复制型结核分枝杆菌的一线药物。 最初开发用于抑制人类转化生长因子受体 (TGFβR)，这是一种途径 与结核病免疫有关，我们还试图测试抑制 TGFβR 是否介导宿主定向活性 我们发现 TGFβR 的基因删除和化学抑制显着减少了细菌。 我们发现，缺乏 TGFβR 的 T 细胞的相互作用能力有所增强。 与 Mtb 感染的巨噬细胞同源，并在肺部感染部位产生 IFNγ。 初步研究为为什么 T 细胞对 Mtb 的反应是长期存在的问题提供了新的答案 感染部位的不足，凸显了 TGFβ 信号传导是新的 HDT 靶点的可能性。 我们鉴定出具有两种独立活性的化合物，既可以杀死结核分枝杆菌，又可能阻止其出现 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。 在宿主方面，我们负责杀死结核分枝杆菌，从而直接识别出耐药性的新靶标。 将确定 TGFβR 信号在 Mtb 感染中的作用 最后，我们将测试这种双重宿主-病原体靶向。 通过测试我们的化合物在体内的功效来制定策略。