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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

基本信息

批准号：
10613896
负责人：
Thomas Dick
金额：
$ 70.34万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10613896
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 Phenotype Population Positioning Attribute Predisposition 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 chemotherapy clinical development clinically relevant cystic fibrosis patients drug discovery drug testing efficacy study efficacy testing fighting follow-up improved in vivo innovation lead optimization member mouse model new chemical entity new therapeutic target non-tuberculosis mycobacteria novel novel therapeutics pathogen patient population pharmacologic potency testing pre-clinical preclinical development prognostic programs scaffold success transmission process tuberculosis treatment uptake

项目摘要

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