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: 10394991
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394991
• 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; 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.

抽象的 结核病（结核病）的发病率正在降低，但由于结核分枝杆菌的亲属而引起的疾病，一种 本质上抗性细菌称为“无结核（非TB）分枝杆菌”或NTM，正在增加。 这些新兴的NTM病原体专门威胁着脆弱的群体，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种抗生素的化学疗法 如果可以治愈，则可以治愈。最有问题的NTM病原体是脓肿分枝杆菌（MAB）。 mab 肺部疾病被认为无法治愈，死亡率可能超过50％。据认为mab感染是 仅从环境来源获得。但是，最近证明了mab变成了 可以从人到人传播。紧急医疗需要对新的抗生素作用 “超级烤”。从头 - 新化学实体 /新目标 - 药物发现需要10年或更长时间才能带来 对患者的新药物。新抗生素的另一种方法是“重新定位”退出药物。一些 但是，抗生素对NTM显示了一些活性，但是，诸如低效力和毒性极限或排除等问题 他们的临床用途。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 该行动反对具有物理验证的目标，但已针对以外的传染病开发 NTM。由于这些药物类别包括FDA批准的成员，因此损耗率较低，并且 成功的概率高于从头毒品发现产生的可能性。例如，恶唑烷酮 lineZolid（靶核糖体）显示出一些抗MAB活性，但效力低下。在屏幕中 奥恶唑烷酮库和默克的后续表征工作我们已经确定了铅化合物 提高效力并降低毒性，从而验证策略。同样，利福米霉素利福平（靶标 RNA聚合酶）对MAB的活性不佳。我们鉴定出利福霉素铅化合物有改善 效力。在这里，我们将使我们的两个引线进行优化运动，以提供临床前开发 在已建立和新颖的MAB肺疾病的小鼠模型中具有耐受性，暴露和效率的候选者。 但是，NTM感染模型确实存在，但是它们在很大程度上依赖于免疫缺陷的小鼠菌株和全身性菌株 感染方法，而自然传播是通过吸入发生的。重要的是，当前模型显示有限 病理学与人NTM肺部疾病的相似之处。需要强大的预测鼠标模型。 标准小鼠菌株主要抵抗MAB感染并清除细菌。在初步工作中 我们针对不同的野生型小鼠菌株测试了一小撮临床mAb分离株，可能表明有些 组合可改善细菌的生长和病理。与我们的两个领先优化项目平行 （AIM 1和2），我们将开发和利用改进的MAB鼠标模型（AIM 3）。总之，我们的工作将 提供临床前开发候选者，以进展为mab肺疾病的临床发育和A 更健壮和预测的鼠标模型。