Lesion-centric imaging and PK-PD of pyrazinamide for TB/HIV co-infection

吡嗪酰胺治疗 TB/HIV 合并感染的病灶中心成像和 PK-PD

• 批准号: 8894383
• 负责人: Veronique Dartois
• 金额: $ 78.89万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894383
• 关键词: Address; Affect; Antibiotics; Antitubercular Agents; Asses; Bacillus (bacterium); Bacteria; Biodistribution; Biological Markers; Chronic; Collaborations; Complex; Coupled; Data; Development; Diffuse; Disease; Disease Progression; Dose; Drug Combinations; Drug Design; Drug Exposure; Drug Interactions; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug-sensitive; Exposure to; Failure; Functional disorder; Future; Gastrointestinal tract structure; Genetic; Genus Mycobacterium; Goals; Granuloma; HIV; HIV Seropositivity; Heterogeneity; Human; Image; Immune; In Vitro; Individual; Infection; Kinetics; Knowledge; Lesion; Link; Liquid Chromatography; Location; Lung; Maps; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Biotransformation; Modeling; Molecular Target; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nature; Necrosis; Necrotic Lesion; Nodule; Oryctolagus cuniculus; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Physiology; Plant Roots; Population; Predisposition; Property; Pyrazinamide; Reading; Regimen; Relapse; Relative (related person); Resected; Resolution; Sampling; Site; Solid; Spatial Distribution; Sterilization; Testing; Therapeutic; Time; Tissues; Translating; Tuberculosis; United States National Institutes of Health; active method; bactericide; base; cell killing; chemotherapy; co-infection; cytokine; design; disease transmission; drug development; drug distribution; effective therapy; extracellular; improved; killings; metabolomics; mutant; pathogen; patient population; pharmacokinetic model; prevent; programs; public health relevance; pyrazinamide deamidase; pyrazinoic acid; quantum; stem; tandem mass spectrometry; tuberculosis drugs; tuberculosis treatment; two-dimensional

DESCRIPTION: In HIV-positive individuals, the chances of reactivation of tuberculosis (TB) infection, failure of active TB disease or relapse are higher than in immune competent populations. Anti-TB chemotherapy must fully sterilize all infection sites given the cytokine dysregulation and global immune perturbations. Pyrazinamide (PZA) is a mainstay of nearly all chemotherapies for drug-sensitive and drug-resistant tuberculosis (TB) and only TB drug capable of accelerating the sterilization of most forms of TB. Despite its therapeutic importance, we lack knowledge of its biodistribution within and among affected lesions, as well as the fates and actions of PZA both at these sites and within the mycobacterium itself. The extensive heterogeneity of TB lesions, in terms of drug penetration, pathophysiology, and susceptibility of the bacilli, is considered a major cause of persistence leading to relapse or reactivation. To achieve the next 'quantum leap' in TB control programs and effectively prevent TB activation in HIV patient populations, we must design drug regimens made of antibiotics that have complementary distribution in the various niches where bacilli are found within granulomas. The focus on PZA to develop shorter and more effective therapies for TB-HIV stems from our observations that several drug classes diffuse poorly or not at all into necrotic tissues and caseum, while PZA appears to accumulate preferentially in this niche where persisters are suspected to reside. We take advantage of the rabbit models of chronic cavitary and latent TB, which together recapitulate the spectrum of human pulmonary lesions, to expand our mechanistic understanding of PZA's unique sterilizing activity. We have recently developed and applied imaging mass spectrometry and intrabacterial metabolomic platforms with Mycobacterium tuberculosis (Mtb) to measure the lesion-specific distribution and bio- activation of PZA, and discovered previously unsuspected fates of PZA that may contribute to its sterilizing properties. The specific goals of this proposal are (1) to define the biodistribution and metabolic fate of PZA as it transits from the gastrointestinal tract, to the center of necrotic granulomas where its target bacterial population, to its molecular targets within Mtb itself, and (2) to asses the potential of PZA in killing specific bacterial populations suspected of being involved in relapse, reactivation of latent TB, cavitary disease progression, and disease transmission. We propose to conduct lesion-centric PK-PD studies with human-equivalent doses of PZA in the latent and progressive cavitary rabbit models. Combined data of penetration and bactericidal activities in specific lesions will inform the rational design of future drug regimens containing PZA as well as the most effective timing of PZA therapy against TB-HIV.

描述：在 HIV 阳性个体中，结核病 (TB) 感染重新激活、活动性结核病失败或复发的几率高于免疫能力强的人群。鉴于细胞因子失调和整体免疫扰动，抗结核化疗必须完全消毒所有感染部位。吡嗪酰胺 (PZA) 是几乎所有药物敏感和耐药结核病 (TB) 化疗的支柱，也是唯一能够加速大多数结核病灭菌的结核病药物。尽管它具有治疗重要性，但我们对其在受影响病变内部和之间的生物分布以及 PZA 在这些部位和分枝杆菌本身的命运和作用缺乏了解。就药物渗透、病理生理学和杆菌敏感性而言，结核病灶的广泛异质性被认为是导致复发或再激活的持续存在的主要原因。为了实现结核病控制计划的下一个“量子飞跃”并有效防止艾滋病毒患者群体中的结核病激活，我们必须设计由抗生素组成的药物治疗方案，这些抗生素在肉芽肿内发现杆菌的各个生态位中具有互补分布。对 PZA 开发更短、更有效的 TB-HIV 疗法的关注源于我们的观察，即几种药物类别扩散不良或根本不扩散到坏死组织和酪蛋白中，而 PZA 似乎优先在怀疑持续存在的这个生态位中积累。我们利用慢性空洞和潜伏性结核病的兔模型，这些模型共同概括了人类肺部病变的范围，以扩大我们对 PZA 独特杀菌活性的机制理解。我们最近开发并应用了成像质谱法和结核分枝杆菌（Mtb）的细菌内代谢组学平台来测量 PZA 的病变特异性分布和生物活化，并发现了以前未曾怀疑的 PZA 命运，这可能有助于其灭菌特性。该提案的具体目标是（1）定义生物分布和代谢 PZA 从胃肠道转移到坏死肉芽肿中心（其目标细菌群所在）、Mtb 本身内的分子目标时的命运，以及 (2) 评估 PZA 杀死疑似涉及的特定细菌群的潜力复发、潜伏结核病重新激活、空洞疾病进展和疾病传播。我们建议在潜伏性和进行性空洞兔模型中使用人体等效剂量的 PZA 进行以病变为中心的 PK-PD 研究。特定病变中渗透和杀菌活性的综合数据将为未来包含 PZA 的药物方案的合理设计以及 PZA 治疗 TB-HIV 的最有效时机提供信息。