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

描述：在hiv阳性个体中，结核病（TB）感染再激活、活动性结核病失败或复发的机会高于免疫正常人群。鉴于细胞因子失调和全局免疫扰动，抗结核化疗必须充分消毒所有感染部位。吡嗪酰胺（PZA）是几乎所有药物敏感和耐药结核病（TB）化疗的主要药物，也是唯一能够加速大多数结核病灭菌的结核病药物。尽管其具有重要的治疗意义，但我们缺乏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的知识。结核病病变在药物渗透、病理生理和杆菌易感性方面的广泛异质性被认为是导致复发或再激活的持续性的主要原因。为了实现结核病控制规划的下一个“量子飞跃”，并有效预防艾滋病毒患者人群中的结核病活化，我们必须设计由抗生素组成的药物方案，使其在肉芽肿内发现杆菌的各种生态位中具有互补分布。关注PZA以开发更短、更有效的治疗结核- hiv的方法源于我们的观察，即几种药物在坏死组织和病例中扩散很差或根本无法扩散，而PZA似乎优先积聚在这个被怀疑存在持续性的利基中。我们利用兔慢性空洞性和潜伏性结核病模型，共同概括了人类肺部病变的频谱，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结核分枝杆菌（Mtb）的成像质谱和细菌内代谢组学平台来测量PZA的病变特异性分布和生物激活，并发现了PZA以前未预料到的命运，可能有助于其灭菌特性。本提案的具体目标是(1)定义生物分布和代谢

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.