Development of Novel Therapeutics for Treatment of Mycobacterial Infections

治疗分枝杆菌感染的新疗法的开发

基本信息

批准号：
10452477
负责人：
Elton Jeffrey North
金额：
$ 25.22万
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：
2021-03-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10452477
关键词：
Acetamides Aerobic Affect Age Amikacin Aminoglycosides Animals Anti-Bacterial Agents Antibiotics Antimycobacterial Agents Antitubercular Agents Auditory Binding Proteins Biological Biological Assay Biological Availability Cell Line Cells Cochlea Complex Computer Assisted Data Development Drug Design Drug Kinetics Drug resistant Mycobacteria Tuberculosis Ensure Evaluation Exhibits FDA approved Future Gender Genus Mycobacterium Goals Gram-Negative Bacteria Hearing Human In Vitro Individual Indoles Infection Kidney Lead Ligands Lung diseases Membrane Proteins Methodology Methods Multidrug-Resistant Tuberculosis Mus Mycobacterium Infections Mycobacterium abscessus Mycobacterium tuberculosis Mycolic Acid Oral Orthologous Gene Patients Peripheral Permeability Pharmacology Plasma Proteins Property Race Running Series Solubility System Testing Toxic effect Vertigo Zebrafish absorption antimicrobial bactericide base cystic fibrosis patients cytotoxic cytotoxicity design drug candidate drug development experience hearing impairment hearing loss risk improved in vivo inhibitor lead candidate mouse model mycobacterial non-tuberculosis mycobacteria novel novel therapeutics ototoxicity pathogen prevent side effect small molecule systemic toxicity tubular necrosis

项目摘要

Aminoglycosides (AG) have broad antibiotic spectra against aerobic gram-positive and gram-negative bacteria and mycobacterial pathogens. AG toxicities include kidney tubular necrosis, vertigo, and, most notably, hearing loss. Regarding the use of AG in mycobacterial infections, they are used to treat multidrug-resistant tuberculosis (MDR-TB) and Mycobacterium abscessus complex (MABSC) infected patients with cystic fibrosis (or other structural lung disorders). Studies have shown that 55-58% of patients infected with MDR-TB who received amikacin as part of their therapy, experienced hearing loss due to its ototoxic effects. Likewise, up to 27% of patients with cystic fibrosis infected with M. abscessus who received aminoglycoside therapy experienced hearing loss. To date, there is no FDA-approved method or therapy available to prevent or treat hearing loss. Reduced reliance on aminoglycoside use in mycobacterial infections should minimize hearing loss risk for patients infected with drug-resistant Mycobacterium tuberculosis (M. tb) strains and nontuberculous (NTM) mycobacteria. We have discovered a novel series of small molecules (indole-2-carboxamides and acetamides) that have potent activity against a panel of mycobacteria. Two of our lead candidates had poor oral absorption yet achieved efficacy in a mouse model of M. abscessus infection. Therefore, we propose to discover and develop antimycobacterial inhibitors with potent activity with improved pharmacokinetic profiles and no ototoxicity. This will be accomplished using ligand-based drug design and computer aided drug design. In vitro bioavailability and toxicity profiles will also be determined for the inhibitors. Finally, potent anti-NTM agents with optimized bioavailability and toxicity profiles will be subjected to macromolecular mechanism of action studies, ensuring future compounds remain on target as Mycobacterial membrane protein Large 3 (MmpL3) inhibitors.

氨基糖苷类 (AG) 对需氧革兰氏阳性菌和革兰氏阴性菌具有广泛的抗菌谱和分枝杆菌病原体。 AG 毒性包括肾小管坏死、眩晕，尤其是听力损失损失。关于 AG 在分枝杆菌感染中的应用，它们用于治疗多重耐药性结核病（MDR-TB）和脓肿分枝杆菌复合体（MABSC）感染的囊性纤维化患者（或其他结构性肺部疾病）。研究表明，55-58% 的耐多药结核病患者接受阿米卡星作为治疗的一部分，由于其耳毒性作用而出现听力损失。同样，直到 27% 的囊性纤维化患者感染脓肿分枝杆菌，接受氨基糖苷类药物治疗经历过听力损失。迄今为止，尚无 FDA 批准的方法或疗法可用于预防或治疗听力损失。减少分枝杆菌感染对氨基糖甙类药物的依赖应能最大程度地减少感染耐药结核杆菌 (M. tb) 菌株的患者存在听力损失风险，以及非结核分枝杆菌（NTM）。我们发现了一系列新颖的小分子（吲哚-2-甲酰胺和乙酰胺），它们具有有效的作用针对一组分枝杆菌的活性。我们的两位主要候选人口服吸收较差，但尚未实现在脓肿分枝杆菌感染小鼠模型中的疗效。因此，我们建议发现和开发抗分枝杆菌药物具有有效活性的抑制剂，具有改善的药代动力学特征且无耳毒性。这将使用基于配体的药物设计和计算机辅助药物设计来完成。体外生物利用度和还将确定抑制剂的毒性特征。最后，经过优化的有效抗 NTM 药物生物利用度和毒性特征将接受大分子作用机制研究，确保未来的化合物仍以分枝杆菌膜蛋白大 3 (MmpL3) 抑制剂为目标。