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

描述：在艾滋病毒阳性的个人中，结核病(TB)感染重新激活、活动性结核病失败或复发的机会高于具有免疫能力的人群。考虑到细胞因子失调和全球免疫紊乱，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)化疗的主要药物，也是唯一能够加速大多数形式结核病的绝育的结核病药物。尽管PZA具有重要的治疗作用，但我们缺乏对其在病变内和病变之间的生物分布，以及PZA在这些部位和分枝杆菌本身的命运和作用的了解。就药物渗透性、病理生理学和细菌的敏感性而言，结核病病变的广泛异质性被认为是导致复发或重新激活的持久性的主要原因。为了在结核病控制计划中实现下一次“量子飞跃”，并有效地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制成的药物方案，这些药物方案在肉芽肿内发现细菌的各种利基环境中具有互补分布。关注PZA以开发更短、更有效的结核病-艾滋病毒疗法源于我们的观察，即几种药物类别在坏死组织和干酪中扩散很差或根本不扩散，而PZA似乎优先在这一怀疑持久者居住的利基市场积累。我们利用慢性空洞性和潜伏性结核病的兔模型，共同概括了人类肺部病变的谱，以扩展我们对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仪和结核分枝杆菌(Mtb)的细菌内代谢平台来测量PZA的皮损特异性分布和生物活性，并发现了可能有助于其灭菌性能的以前未被怀疑的PZA命运。这项提案的具体目标是：(1)确定生物分布和代谢 在PZA从胃肠道转移到坏死性肉芽肿中心(其目标细菌群在那里)和它在结核杆菌自身内的分子靶点时的命运，以及(2)评估PZA在杀死被怀疑参与复发、潜伏性结核病重新激活、空洞性疾病进展和疾病传播的特定细菌群方面的潜力。我们建议在潜伏期和进展性空洞兔模型中，使用等量的PZA进行以病变为中心的PK-PD研究。结合特定皮损的渗透率和杀菌活性的数据，将为未来含有PZA的药物方案的合理设计以及PZA治疗结核病-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.