Development of Novel Therapeutics for Treatment of Mycobacterial Infections

治疗分枝杆菌感染的新疗法的开发

• 批准号: 10579977
• 负责人: Elton Jeffrey North
• 金额: $ 22.78万
• 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: 2021-03-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579977
• 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; Microsomes; Multidrug-Resistant Tuberculosis; Multiple drug resistant Mycobacteria Tuberculosis; Mus; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium tuberculosis; Mycolic Acid; Oral; Orthologous Gene; Patients; Peripheral; Permeability; Plasma Proteins; Property; Race; Running; Series; Solubility; System; Testing; Toxic effect; Vertigo; Zebrafish; absorption; antimicrobial; bactericide; 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; pharmacologic; prevent; side effect; small molecule; systemic toxicity; tubular necrosis

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（Ag）具有针对有氧革兰氏阳性和革兰氏阴性细菌的广泛抗生素光谱 和分枝杆菌病原体。 AG毒性包括肾小管坏死，眩晕，最值得注意的是听力 损失。关于在分枝杆菌感染中使用Ag，它们用于治疗多种药物 结核病（MDR-TB）和分枝杆菌脓肿复合物（MABSC）感染囊性纤维化患者 （或其他结构性肺部疾病）。研究表明，感染MDR-TB的患者中有55-58％ 作为治疗的一部分，接受了amikacin，由于其耳毒性作用而经历了听力损失。同样，要 27％的囊性纤维化患者感染了接受氨基糖苷疗法的脓肿的脓肿。 经历了听力损失。迄今为止，还没有FDA批准的方法或治疗可预防或 治疗听力损失。减少对分枝杆菌感染中氨基糖苷使用的依赖应最小化 感染耐药性分枝杆菌（M. TB）菌株的患者的听力损失风险和 非结核（NTM）分枝杆菌。 我们发现了一系列新型的小分子（吲哚-2-羧化酰胺和乙酰胺），它们具有有效的 针对分枝杆菌小组的活动。我们的两个主要候选人的口服吸收较差 脓肿的小鼠模型中的功效。因此，我们建议发现和开发抗菌细菌 具有有效活性的抑制剂，具有改善的药代动力学特征并且没有耳毒性。这会 可以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谱。最后，具有优化的有效抗NTM药物 生物利用度和毒性特征将受到作用研究的大分子机制，以确保 未来的化合物仍然是分枝杆菌膜蛋白大3（MMPL3）抑制剂。