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

产品说明：在艾滋病毒抗体阳性者中，结核病感染复发、活动性结核病治愈或复发的机会高于免疫能力正常的人群。鉴于细胞因子失调和整体免疫紊乱，抗结核化疗必须完全消除所有感染部位。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形式TB灭菌的TB药物。尽管其治疗的重要性，我们缺乏知识，其生物分布内和之间的受影响的病变，以及命运和行动的PZA在这些网站和内的分枝杆菌本身。结核病病灶在药物渗透、病理生理学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计划的下一个“量子飞跃”，并有效预防艾滋病毒患者人群中的结核病激活，我们必须设计由抗生素组成的药物方案，这些抗生素在肉芽肿中发现杆菌的各种小生境中具有互补分布。对PZA的关注是为了开发更短和更有效的TB-HIV疗法，这源于我们的观察，即几种药物类别在坏死组织和酪蛋白中的扩散很差或根本没有扩散，而PZA似乎优先在这个怀疑存在持久性的小生境中积累。我们利用慢性空洞和潜伏性TB的兔模型，它们共同概括了人类肺部病变的谱，以扩展我们对PZA独特的杀菌活性的机制理解。我们最近开发并应用了成像质谱和结核分枝杆菌（Mtb）的细菌内代谢组学平台，以测量PZA的病变特异性分布和生物活化，并发现了可能有助于其灭菌特性的PZA的先前未被怀疑的命运。该提案的具体目标是（1）确定生物分布和代谢 当PZA从胃肠道转移到其靶细菌群体所在的坏死性肉芽肿中心，转移到Mtb本身内的分子靶标时，PZA的命运，以及（2）评估PZA在杀死怀疑参与复发、潜伏性TB再活化、空洞性疾病进展和疾病传播的特定细菌群体中的潜力。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。结合特定病变中的渗透和杀菌活性的数据将为未来含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。

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.