Inhaled pyrazinoic acid for tuberculosis therapy

摘要 结核病（TB）是一个严重的世界卫生问题。结核病每年造成150万人死亡， 据信，全球三分之一的人口感染了结核分枝杆菌（Mtb）， TB的代理人。控制结核病的一个主要挑战是多药耐药和广泛耐药（MDR）的增加 和XDR）Mtb菌株。由于其显著的杀菌活性以及与其它杀菌剂的协同活性， 吡嗪酰胺（PZA）是目前治疗药物敏感性结核病的四种药物方案的关键组成部分， 也包括在耐多药结核病的许多治疗方案中。然而，PZA的未来效用岌岌可危 因为抗PZA结核菌株的增加。PZA是一种前药， 吡嗪酰胺酶PncA对吡嗪酸（POA）的抑制作用，以及最常见的PZA耐药Mtb 菌株在pncA基因中具有突变。作为PZA的替代品，直接给药吡嗪酸（POA） 已经被提议了。 在这篇R21中，我们建议使用豚鼠评估吸入POA作为结核病的预防治疗 模型通过直接将药物输送到肺部，在结核分枝杆菌感染部位局部高浓度， 可以达到全身低剂量。在目标1中，我们将进行干粉的药代动力学（PK）研究 通过吸入递送给豚鼠的POA气雾剂。在目标2中，我们将进行有效性实验， 评估吸入POA作为治疗豚鼠结核病的连续疗法的效果。合并结果 目的1和2的研究将检验我们的假设，即通过以下方法可以在肺和气道中实现高水平的POA： 吸入疗法和用吸入POA作为标准疗法补充的治疗将显著 减少结核分枝杆菌的器官负担和结核病的病程。 我们的方案具有很高的临床意义 并有可能揭示吸入POA作为治疗药物敏感性结核病的一种新的连续疗法， PZA是一种重要的结核病药物。

Abstract Tuberculosis (TB) represents a severe world health problem. TB accounts for 1.5 million deaths annually and a third of the global population is believed to be infected with Mycobacterium tuberculosis (Mtb), the causative agent of TB. A major challenge to controlling TB is the rise in multidrug and extensively drug resistant (MDR and XDR) Mtb strains. Because of its remarkable sterilizing activity as well as synergistic activity with other drugs, pyrazinamide (PZA) is a critical component of the current four drug regimen for drug sensitive TB and it is also included in many treatment regimens for MDR-TB. However, the future utility of PZA is in jeopardy because of the rise in PZA resistant Mtb strains. PZA is a prodrug that is converted to the active moiety pyrazinoic acid (POA) by the pyrazinamidase PncA, and the most common category of PZA-resistant Mtb strains harbor mutations in the pncA gene. As an alternative to PZA, direct dosing with pyrazinoic acid (POA) has been proposed. In this R21, we propose to evaluate inhaled POA as an adjunctive therapy for TB using a guinea pig model. By directly delivering drug to the lungs, locally high concentrations at the site of Mtb infection but systemically low doses can be achieved. In Aim 1 we will perform pharmacokinetic (PK) studies of dry powder aerosols of POA delivered by inhalation to guinea pigs. In Aim 2 we will perform an efficacy experiment to assess the effect of inhaled POA as an adjunctive therapy for treating TB in guinea pigs. The combined results of Aims 1 and 2 will test our hypotheses that high levels of POA can be achieved in the lungs and airway by inhaled therapy and that treatment with inhaled POA as a supplement to standard therapy will significantly reduce the organ burden of Mtb bacteria and the course of TB disease. Our plan has high clinical significance and potential to reveal inhaled POA as a new adjunctive therapy for treating drug sensitive TB and an approach for rescuing the use of PZA as an important class of TB drug.