Discovery of Novel Nontuberculous Inhibitors

新型非结核抑制剂的发现

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要非结核分枝杆菌 (NTM) 是环境中广泛存在的病原体，可导致进行性肺部疾病以及皮肤和软组织、中枢神经系统和播散性感染。全球 NTM 感染率正在上升，并已成为全球重要的人类病原体。造成这些感染的特定病原体属于以下两个物种之一：i) 脓肿分枝杆菌（脓肿分枝杆菌）复合体（MABSC）和 ii) 鸟分枝杆菌（M. avium）复合体。复合体由脓肿分枝杆菌、马斯林分枝杆菌和博氏分枝杆菌亚种组成，已成为重要的全球威胁导致结构性肺患者肺部感染人数不断增加慢性阻塞性肺病、支气管扩张和囊性纤维化（CF）等疾病。令人担忧的是，合并感染 MABSC 病原体的 CF 患者通常无法治疗，尽管经过多年治疗联合治疗导致 60-70% 的治疗失败，因此，新型抗 NTM 药物具有强效。针对 MABSC 菌株的活性，可以缩短治疗时间，降低耐药率，并改善强烈需要功效。我们发现了一系列新型吲哚-2-甲酰胺 (IC)，它们具有有效的最小抑制剂针对临床感兴趣的各种缓慢和快速生长的 NTM，浓度 (MIC) 值为 0.0039 - 8 µg/ml，包括脓肿分枝杆菌、马西分枝杆菌、博氏分枝杆菌和龟分枝杆菌。此外，IC 在体外和体内均有效。然而，IC 具有亲脂性且水溶性较差。为了避免这种不良的药代动力学特性，我们建议进行设计。新型氨基酸IC类似物并开发载药脂质体，这是一种安全有效的选择将评估新型类似物的抗分枝杆菌活性和活性。化合物将进行一系列 ADMETox 测定以确定推定的 PK/PD 作用。装载的脂质体将被设计用于吸入给药并被设计为优先被吸收通过巨噬细胞，NTM 病原体驻留在受感染的患者体内。 IC 的合成、载药脂质体的生产以及药物释放和巨噬细胞的表征脂质体将使用薄膜水合方法生产，随后使用 IC 装载。脂质体的层状将通过 31P NMR 监测并用确认。将进行冷冻 TEM 研究以确保释放治疗性 IC 浓度。（浓度高于 MIC 值）最后，将进行具有优化药物释放的 IC 负载脂质体。这将使用荧光标记的 IC 负载脂质体进行。巨噬细胞表达 GFP 以可视化摄取和 TEM。