New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis

摘要 虽然结核病(TB)的发病率在下降，但由结核分枝杆菌亲属引起的疾病 被称为“非结核分枝杆菌”或NTM的一组内在耐药细菌正在增加。 这些新出现的NTM病原体特别威胁到弱势群体，包括囊性纤维化患者和 人口老龄化。NTM病的治疗可能需要数年的化疗和多种抗生素 如果治愈了，就治愈了。最有问题的NTM病原体是脓肿分枝杆菌(Mab)。单抗 肺部疾病被认为是不可治愈的，死亡率可能超过50%。人们认为单抗感染是 完全从环境来源获得。然而，最近有证据表明，Mab成为了 可在人与人之间传播。医学上迫切需要一种新的抗生素来对抗这种疾病。 “超级虫子”。从头开始--即新的化学实体/新的靶点--药物发现需要10年或更长时间才能带来 为患者提供新药。使用新抗生素的另一种方法是对现有药物进行“重新定位”。几个 然而，抗生素对NTM表现出一定的活性，但效力低和毒性限制或排除了这些问题 它们的临床应用。我们将“重新定位”称为抗生素类的病原体特定化学优化。 这些药物作用于药物验证的靶点，但已被开发用于治疗非传染性疾病 新台币。由于这些药物类别包括FDA批准的成员，因此磨损率较低， 成功的可能性高于从头发现药物的可能性。例如，恶唑烷酮 利奈唑胺(靶向核糖体)具有一定的抗单抗活性，但效价低，毒性大。在以下屏幕中 恶唑烷酮文库和与默克公司的后续表征工作我们已经确定了先导化合物 提高了效力，降低了毒性，从而验证了这一战略。同样，利福霉素、利福平(靶标 RNA聚合酶)对单抗的活性很低。我们鉴定出利福霉素先导化合物显示出改进的 威力。在这里，我们将对我们的两个销售线索进行优化活动，以提供临床前开发 在已建立的和新的单抗肺病小鼠模型中，具有耐受性、暴露和有效性的候选者。 NTM感染模型确实存在，然而，它们在很大程度上依赖于免疫缺陷的小鼠品系和系统性 感染途径，而自然传播通过吸入发生。重要的是，目前的模型显示有限 病理上与人类NTM肺病相似。需要健壮的、更具预测性的老鼠模型。 标准的小鼠品系大多对单抗感染具有抵抗力，并能清除细菌。在前期工作中 我们测试了一组针对不同野生型小鼠品系的临床单抗分离株，并可以显示出一些 它们的组合可以改善细菌的生长和病理。与我们的两个领先优化项目并行 (目标1和目标2)，我们将开发和利用改进的单抗小鼠模型(目标3)。总之，我们的工作将 为Mab肺部疾病的临床开发提供临床前开发候选方案 更健壮和更具预测性的鼠标模型。

Abstract Whereas tuberculosis (TB) incidence is decreasing, disease due to relatives of Mycobacterium tuberculosis, a group of intrinsically resistant bacteria called ‘Non-tuberculous (non-TB) Mycobacteria’ or NTM, is increasing. These emerging NTM pathogens specifically threaten vulnerable groups, including cystic fibrosis patients and aging populations. Treatment of NTM disease can require years of chemotherapy with multiple antibiotics to achieve cure, if cure is achieved. The most problematic NTM pathogen is Mycobacterium abscessus (Mab). Mab lung disease is considered not curable and death rates can exceed 50%. It was thought that Mab infections are acquired exclusively from environmental sources. However, recently it was demonstrated that Mab became transmittable from human to human. There is an urgent medical need for new antibiotics that work against this ‘super-bug’. De novo - i.e. new chemical entities / new target - drug discovery takes 10 years or more to bring new medicines to patients. An alternative approach to new antibiotics is ‘repositioning’ of exiting drugs. Several antibiotics show some activity against NTM, however, issues such as low potency and toxicity limit or preclude their clinical use. We refer to ‘repositioning’ as the pathogen-specific chemical optimization of antibiotic classes that act against pharmacologically validated targets, but have been developed for infectious diseases other than NTM. Since these drug classes include members that are FDA-approved, attrition rates are lower and the probability of success is higher than incurred through de novo drug discovery. For instance, the oxazolidinone linezolid (target ribosome) shows some anti-Mab activity but suffers from low potency and toxicity. In screens of oxazolidinone libraries and follow-up characterization work with Merck we have identified lead compounds with improved potency and reduced toxicity, thus validating the strategy. Similarly, the rifamycin rifampicin (target RNA polymerase) shows poor activity against Mab. We identified rifamycin lead compounds exhibiting improved potency. Here, we will subject our two leads to optimization campaigns to deliver preclinical development candidates with tolerability, exposure and efficacy in established and novel mouse models of Mab lung disease. NTM infection models do exist, however, they largely rely on immune-deficient mouse strains and a systemic infection approach, whereas natural transmission occurs by inhalation. Importantly, current models show limited similarities in pathology to human NTM lung disease. Robust, more predictive mouse models are needed. Standard mouse strains are mostly resistant against Mab infections and clear the bacterium. In preliminary work we tested a small set of clinical Mab isolates against different wild type mouse strains and could show that some combinations deliver improved bacterial growth and pathology. In parallel to our two lead optimization projects (aim 1 and 2), we will develop and utilize improved Mab mouse models (aim 3). In conclusion, our work will deliver preclinical development candidates for progression to clinical development for Mab lung disease and a more robust and predictive mouse model.