Discovery of Novel Nontuberculous Inhibitors

新型非结核抑制剂的发现

• 批准号: 10291635
• 负责人: Elton Jeffrey North
• 金额: $ 36.38万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291635
• 关键词: Adolescent; Adverse effects; Amikacin; Amines; Amino Acids; Antibiotics; Antimycobacterial Agents; Biological; Biological Assay; Bronchiectasis; Bypass; Cells; Chemicals; Chronic; Chronic Obstructive Airway Disease; Clinical; Combined Modality Therapy; Complex; Cystic Fibrosis; Development; Dose; Drug Kinetics; Encapsulated; Engineering; Ensure; Environment; FDA approved; Film; Formulation; Genus Mycobacterium; Goals; Hemolysis; Hydration status; Hydrophobicity; In Vitro; Indoles; Infection; Infectious Skin Diseases; Inflammatory; Inhalation; Inhalation Drug Administration; Intravenous; Label; Lead; Lipid Bilayers; Liposomes; Lung; Lung diseases; Lung infections; Methodology; Methods; Minimum Inhibitory Concentration measurement; Monitor; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium avium Complex; Mycobacterium chelonae; Neuraxis; Oral; Particle Size; Patients; Pharmaceutical Preparations; Phospholipids; Plasma; Property; Publishing; Recommendation; Resistance; Series; Skin Tissue; Solubility; Structure; Synthesis Chemistry; Therapeutic; Thinness; Time; Treatment Failure; Vesicle; Water; absorption; amikacin liposome; analog; antimicrobial; aqueous; base; cystic fibrosis patients; cytotoxicity; design; drug production; global health; human pathogen; hydrophilicity; improved; infection rate; inhibitor/antagonist; interest; lead candidate; lipophilicity; lung injury; macrophage; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel; novel therapeutics; pathogen; pharmacokinetics and pharmacodynamics; scaffold; soft tissue; uptake; water solubility

Project Summary/Abstract Non-tuberculous mycobacteria (NTM) are widespread pathogens found in the environment and cause progressive lung disease as well as skin and soft tissue, central nervous system and disseminated infections. NTM infections rates are rising globally and have emerged as important human pathogens globally. The specific pathogens responsible for these infections are part of one of two species, i) Mycobacterium abscessus (M. abscessus) complex (MABSC) and ii) Mycobacterium avium (M. avium) complex. The M. abscessus complex comprises the subspecies M. abscessus, M. massiliense and M. bolletii, has emerged as a significant global threat causing an increasing number of pulmonary infections among patients with structural lung disease such as chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis (CF). Of particular concern, patients with CF co-infected with an MABSC pathogen are often untreatable despite years of combination therapy resulting in 60-70% treatment failures. Therefore, novel anti-NTM agents with potent activity against MABSC strains that can shorten treatment time, decrease resistance rates with improved efficacy are strongly needed. We have discovered a novel series of indole-2-carboxamides (IC) that have potent minimum inhibitor concentration (MIC) values of 0.0039 - 8 µg/ml against various slow- and fast-growing NTM of clinical interest, including M. abscessus, M. massiliense, M. bolletii and M. chelonae. In addition, ICs are effective in vitro and in mice, demonstrating their safe and effective profile. However, ICs are lipophilic and are poorly water soluble resulting in poor oral absorption. To circumvent this poor pharmacokinetic property, we propose to design novel amino-acid based IC analogs and develop drug-loaded liposomes, which are a safe and effective option to formulate poorly soluble ICs. Novel analogs will be evaluated for antimycobacterial activity and active compounds will undergo a series of ADMETox assays to determine putative PK/PD action. IC- and IC-analog- loaded liposomes will be designed for inhalation administration and be engineered to be preferentially taken up by macrophages, where NTM pathogens reside in infected patients. This will be accomplished through synthesis of ICs, production of drug-loaded liposomes and characterization of drug release and macrophage uptake. Liposomes will be produced using thin film hydration method with subsequent IC-loading using passive trapping methods. The lamellarity of the liposomes will be monitored by 31P NMR and confirmed with cryo-TEM. Drug-release studies will be performed to ensure therapeutic IC concentrations are released (concentrations above MIC values). Finally, IC-loaded liposomes with optimized drug-release will be subjected to macrophage uptake studies. This will be performed using a fluorescent labeled IC loaded liposome and macrophages expressing GFP to visualize uptake and TEM.

项目总结/文摘