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

治疗囊性纤维化患者非结核分枝杆菌（NTM）肺部疾病的新药

• 批准号: 9923604
• 负责人: Thomas Dick
• 金额: $ 73.5万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9923604
• 关键词: ADP ribosylation; Aging; Animal Model; Antibiotics; Bacteria; Bacterial Infections; Benchmarking; Biological Assay; Chemicals; Chemistry; Clinical; Collaborations; Collection; Communicable Diseases; DNA-Directed RNA Polymerase; Data; Death Rate; Disease; Drug Kinetics; Drug Tolerance; Exhibits; Extreme drug resistant tuberculosis; FDA approved; Future; Growth; Human; Immune; Immunocompetent; Immunocompromised Host; Incidence; Infection; Inhalation; Knowledge; Lactams; Lead; Libraries; Linezolid; Link; Lung; Lung diseases; Medical; Medicine; Metabolic; Microbial Biofilms; Mitochondrial Proteins; Modeling; Mouse Strains; Multi-Drug Resistance; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium tuberculosis; Natural Resistance; Oxazolidinones; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Probability; Property; Protein Synthesis Inhibition; Publishing; Resistance; Ribosomes; Rifabutin; Rifampin; Rifamycins; SCID Mice; Site; Source; Structure-Activity Relationship; Superbug; Systemic infection; Testing; Therapeutic; Toxic effect; Tuberculosis; Vulnerable Populations; Wild Type Mouse; Work; analog; bacterial metabolism; bacterial resistance; base; chemotherapy; clinical development; clinically relevant; cystic fibrosis patients; drug discovery; drug testing; efficacy study; efficacy testing; fight against; follow-up; improved; in vivo; innovation; lead optimization; member; mouse model; new therapeutic target; non-tuberculosis mycobacteria; novel; novel therapeutics; pathogen; patient population; potency testing; pre-clinical; preclinical development; prognostic; programs; scaffold; success; transmission process; tuberculosis treatment; uptake

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.

摘要 虽然结核病（TB）的发病率正在下降，但由于结核分枝杆菌的亲属， 一组被称为“非结核（非TB）分枝杆菌”或NTM的内在耐药细菌正在增加。 这些新出现的NTM病原体特别威胁弱势群体，包括囊性纤维化患者和 人口老龄化。NTM疾病的治疗可能需要多年的多种抗生素化疗， 治愈，如果治愈。最有问题的NTM病原体是结核分枝杆菌（Mab）。mAb 肺病被认为是不可治愈的，死亡率可超过50%。人们认为单克隆抗体感染是 仅从环境来源获得。然而，最近有证据表明，Mab 可以在人与人之间传播医学上迫切需要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年或更长时间才能实现 给病人的新药。新抗生素的另一种方法是对现有药物进行“重新定位”。几 抗生素对NTM显示出一定的活性，然而，诸如低效力和毒性的问题限制或排除了 其临床应用。我们将“重新定位”称为抗生素类别的病原体特异性化学优化 其作用于经验证的靶标，但已被开发用于除 NTM。由于这些药物类别包括FDA批准的成员，因此流失率较低， 成功的可能性高于通过从头药物发现产生的可能性。例如，恶唑烷酮 利奈唑胺（靶核糖体）显示出一定的抗Mab活性，但具有低效力和毒性。在屏幕上， 恶唑烷酮库和后续表征工作与默克公司，我们已经确定了先导化合物， 提高效力和降低毒性，从而验证该策略。类似地，利福霉素利福平（靶向 RNA聚合酶）显示针对Mab的不良活性。我们鉴定了利福霉素先导化合物， 力量在这里，我们将对我们的两个线索进行优化活动，以提供临床前开发 候选物在已建立的和新的Mab肺病小鼠模型中的耐受性、暴露量和功效。 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小鼠品系和系统性免疫缺陷。 感染途径，而自然传播则通过吸入发生。重要的是，目前的模型显示， 与人类NTM肺病的病理学相似性。需要更强大、更具预测性的小鼠模型。 标准小鼠品系大多对Mab感染具有抗性并清除细菌。在初步工作中 我们测试了一小组针对不同野生型小鼠品系的临床单克隆抗体分离株， 组合提供改善的细菌生长和病理学。与我们的两个领先的优化项目并行 (aim 1和2），我们将开发和利用改进的Mab小鼠模型（目的3）。总之，我们的工作将 为Mab肺病的临床开发提供临床前开发候选药物， 更强大和预测性的小鼠模型。