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）对需氧革兰氏阳性和革兰氏阴性细菌具有广泛的抗菌谱