Preclinical evaluation of compounds that inhibit cholesterol uptake in M. tuberculosis.

抑制结核分枝杆菌胆固醇摄取的化合物的临床前评估。

• 批准号: 9759755
• 负责人: Brian C VanderVen
• 金额: $ 45.66万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759755
• 关键词: Acute; Address; Adenylate Cyclase; Antibiotic Therapy; Antibiotics; Architecture; Assimilations; Attenuated; Bacteria; Bacterial Physiology; Basic Science; Cells; Cessation of life; Chemical Stimulation; Chemicals; Cholesterol; Cholesterol Homeostasis; Complex; Cyclic AMP; Diffusion; Disease; Drug Combinations; Drug Targeting; Genetic Transcription; Goals; Granuloma; Human; Hypoxia; Immune; Immune response; Infection; Inflammation; Inflammatory; Knowledge; Lesion; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Oral; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Positioning Attribute; Production; Regulation; Research; Route; Series; TNF gene; Therapeutic; Time; Tissues; Treatment Protocols; Tuberculosis; Virulence; biological adaptation to stress; cytokine; drug candidate; drug development; drug discovery; efficacy testing; in vivo; inhibitor/antagonist; innovation; macrophage; mouse model; mutant; mycobacterial; novel; novel strategies; novel therapeutics; preclinical evaluation; recruit; response; treatment strategy; tuberculosis drugs; tuberculosis granuloma; tuberculosis treatment; uptake

Project Summary / Abstract Cholesterol metabolism in Mtb is an attractive target for basic research and new drug development efforts. The Mtb cholesterol metabolic pathway is specific to the bacteria and mutants defective in this pathway are attenuated in various infection models. This suggests that chemically inhibiting this pathway will also attenuate Mtb virulence in vivo. We recently discovered a compound series that blocks cholesterol uptake in Mtb and stimulates cAMP overproduction in the bacteria. This is important since cAMP regulates mycobacterial central metabolism, transcription, pathogenicity, dormancy, and stress responses. Thus, chemically stimulating cAMP production in Mtb will perturb multiple different aspects of bacterial physiology in addition to cholesterol utilization. Granulomas are a major pathologic barrier that limits immune cell recruitment and antibiotic diffusion. Within a granuloma Mtb is sequestered in a cholesterol rich and hypoxic microenvironment that is thought to favor bacterial persistence. During infection, MΦ’s produce TNF-α which drives TB tissue pathology and is required to form and maintain granulomas. It is thought that TNF-α depletion can disturb the granuloma architecture and promote enhanced antibiotic availability or disrupt the granuloma microenvironment making TB antibiotics more effective. It has long been known that TNF-α production by MΦ’s can be down regulated in response to high levels of cytosolic cAMP and it is also known that Mtb-derived cAMP down regulates TNF-α production in MΦ’s. Our compound series stimulates enough Mtb-derived cAMP to down regulate TNF-α production at the infected cell level. Thus, stimulating cAMP overproduction in Mtb could be a novel strategy to reduce TNF-α levels specifically in infected MΦ’s to enhance the activity of current TB drugs. Here we propose to characterize the molecular mechanisms of how these probes block cholesterol uptake and stimulate the overproduction of cAMP in Mtb (Aim 1). We also will determine how Mtb-derived cAMP modulates: (i) the host immune response, (ii) MΦ function, and (iii) evaluate the efficacy of V-59 alone and in combination with known TB antibiotics in vivo with a goal of evaluating the therapeutic potential of V-59 (Aim 2). Because we already have a compound that has excellent potency and demonstrates in vivo efficacy via the oral route, we are well positioned to make progress with a potential TB drug candidate and novel treatment strategy.

项目摘要 /摘要 MTB中的胆固醇代谢是基础研究和新药物开发工作的有吸引力的目标。 MTB胆固醇代谢途径是特定于细菌的特异性，在该途径中有缺陷的突变体是 在各种感染模型中减弱。这表明化学抑制此途径也会减弱 MTB病毒在体内。我们最近发现了一个化合物系列，该系列阻止了MTB和 刺激细菌中的cAMP过量生产。这很重要，因为营地调节分枝杆菌中心 代谢，转录，致病性，休眠和应力反应。那是化学刺激的营地 除胆固醇利用外，MTB中的生产还将扰动细菌生理的多个不同方面。 肉芽肿是限制免疫细胞募集和抗生素扩散的主要病理障碍。之内 肉芽肿mtb被认为有利于胆固醇和低氧的微环境中被认为有利于 细菌持久性。在感染期间，Mφ产生TNF-α，该TNF-α驱动TB组织病理学，需要 形成并保持颗粒。据认为，TNF-α部署会干扰肉芽肿架构，并且 促进增强的抗生素可用性或破坏肉芽瘤微环境，使结核病更多 有效的。早就知道，Mφ的TNF-α产生可以响应高 胞质营的水平，也已经知道MTB衍生的cAMP向下调节Mφ中的TNF-α产生。 我们的化合物系列刺激了足够的MTB衍生的营地，以降低受感染的TNF-α产生 细胞水平。这是刺激MTB中的cAMP过量生产可能是降低TNF-α水平的新型策略 特别是在受感染的Mφ中增强当前结核病药物的活性。 在这里，我们建议表征这些问题如何阻止胆固醇吸收的分子机制 并刺激MTB中营地过量生产（AIM 1）。我们还将确定MTB衍生的营地 调节：（i）宿主免疫反应，（ii）Mφ功能，（iii）单独评估V-59的效率 与已知的TB抗生素结合体内，以评估V-59的治疗潜力（AIM 2）。 因为我们已经有一个具有出色效力的化合物，并通过口服证明了体内效率 途径，我们在潜在的结核病药物和新颖的治疗策略方面做得很好，可以取得进步。