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.

项目摘要/摘要 无结核分枝杆菌（NTM）是在环境中发现的广泛病原体，并原因 进行性肺部疾病以及皮肤和软组织，中枢神经系统和传播感染。 NTM感染率在全球范围内正在上升，并且在全球重要的人类病原体中出现。这 造成这些感染的特定病原体是两个物种之一，i）分枝杆菌 （M. abcessus）复合物（MABSC）和II）鸟分枝杆菌（M. avium）复合物。 M. abcessus 复合物包括亚种M. abcessus，M。Massiliense和M. bolletii，已成为显着的 全球威胁导致结构性肺患者的肺部感染数量增加 疾病，例如慢性阻塞性肺部疾病，支气管扩张和囊性纤维化（CF）。特别 令人担忧的是，与MABSC病原体共感染CF的患者通常是无法治疗的目的地年。 联合疗法导致60-70％的治疗失败。因此，具有有效的新型抗NTM药物 针对可以缩短治疗时间的MABSC菌株的活动，随着改善而降低电阻率 强烈需要功效。 我们发现了一系列具有潜在最小抑制剂的新型吲哚-2-羧化酰胺（IC） 浓度（MIC）值为0.0039-8 µg/ml的浓度（MIC）对各种慢慢增长和快速增长的临床感兴趣， 包括M. Abscessus，M。Massiliense，M。Bolletii和M. Chelonae。此外，IC在体外是有效的，并且 在小鼠中，证明其安全有效的特征。但是，IC是亲脂性的，水溶性很差 导致口服滥用差。为了避免这种糟糕的药代动力学特性，我们建议设计 新型基于氨基酸的IC类似物并发展出药物负载的脂质体，这是安全有效的选择 制定不良的IC。将评估新型类似物的抗菌活性和活性 化合物将经过一系列的ADMETOX分析，以确定推定的PK/PD作用。 ic-和ic-analog- 负载的脂质体将设计用于吸入，并设计为优先服用的脂质体 通过巨噬细胞，其中NTM病原体位于感染患者中。这将通过 IC的合成，加载脂质体的产生以及药物释放和巨噬细胞的表征 吸收。脂质体将使用薄膜水合法产生，随后使用IC负载 被动捕获方法。脂质体的层状将通过31p NMR监测，并确认 冷冻-TEM。将进行药物释放研究以确保释放热浓度 （高于MIC值的浓度）。最后，将对具有优化药物释放的IC负载脂质体进行 进行巨噬细胞摄取研究。这将使用荧光标记的IC负载脂质体和 表达GFP的巨噬细胞可视化摄取和TEM。