EFFLUX INHIBITORS FOR MYCOBACTERIUM THERAPIES

用于分枝杆菌治疗的外排抑制剂

• 批准号: 6292881
• 负责人: Penelope N. Markham
• 金额: $ 9.97万
• 依托单位: PROTEZ PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6292881
• 关键词: Mycobacterium tuberculosis; antibiotics; antitubercular agents; chemical structure function; drug design /synthesis /production; macrolide antibiotics; macrophage; membrane transport proteins; multidrug resistance; tetracyclines; tuberculosis

DESCRIPTION (Verbatim from Applicant's Abstract): New drugs are desperately needed for tuberculosis both to reduce the long duration of treatment and to cure and stop transmission of multiple-drug-resistant Mycobacterium tuberculosis. Recent studies, including the completion of the TB genome sequence, suggest that efflux pump inhibitors may play a significant role in the intrinsic resistance of M. tuberculosis to most common antibiotics. Influx has identified several low molecular weight inhibitors of the NorA efflux pump in Staphylococcus aureus which demonstrated synergistic activity with ciprofloxacin and which dramatically reduced the frequency of emergence of ciprofloxacin-resistant mutants. In preliminary in vitro experiments with M. tuberculosis, two of these compounds demonstrated marked synergy when combined with two tetracyclines and a macrolide. We propose to a) test additional congeners of these inhibitors to determine structure-activity relationships with respect to M. tuberculosis, b) determine the substrate specificity of the effected efflux pump by testing for synergy with a wide variety of antimicrobials, c) determine the effect of the inhibitors on the frequency of emergence of drug-resistant mutants and d) with a variety of TB drug-susceptible and resistant clinical isolates, and e) assess synergistic activity of inhibitors with antimicrobial agents in a macrophage model of TB infection. It is anticipated that these studies will result in the identification of one or more lead compounds that would be assessed for activity in animal models of acute and chronic TB in a phase II project. In addition these compounds would serve as starting points for synthesis of additional congeners. PROPOSED COMMERCIAL APPLICATION: The envisioned commercial product is a combination of tetracycline, a macrolide, or possibly another antibiotic with an efflux pump inhibitor. This combination can form a powerful anti-TB agent which can be effective against resistant strains and prevent further emergence of resistance.

描述（逐字摘自申请人摘要）：新药迫切需要 结核病所需的药物既可以缩短治疗时间，又可以 治愈并阻止多重耐药分枝杆菌的传播 结核。最近的研究，包括结核病基因组的完成 序列，表明外排泵抑制剂可能在 结核分枝杆菌对大多数常见抗生素的内在耐药性。涌入 已鉴定出 NorA 外排泵的几种低分子量抑制剂 在金黄色葡萄球菌中表现出协同活性 环丙沙星，大大降低了出现频率 环丙沙星耐药突变体。在 M 的初步体外实验中。 结核病，其中两种化合物联合使用时表现出显着的协同作用 含有两种四环素和一种大环内酯。我们建议 a) 测试额外的 这些抑制剂的同系物以确定结构-活性关系 对于结核分枝杆菌，b) 确定底物特异性 通过测试与多种物质的协同作用来影响外排泵 抗菌剂，c) 确定抑制剂对发生频率的影响 耐药突变体的出现和 d) 多种结核病 药物敏感和耐药的临床分离株，以及 e) 评估协同作用 结核病巨噬细胞模型中抗菌药物抑制剂的活性 感染。预计这些研究将导致 鉴定一种或多种将被评估的先导化合物 第二阶段项目中急性和慢性结核病动物模型的活动。在 此外，这些化合物将作为合成的起点 额外的同系物。 拟议的商业应用： 设想的商业产品是四环素、大环内酯或 可能是另一种具有外排泵抑制剂的抗生素。 这种组合可以形成 强效抗结核剂，可有效对抗耐药菌株并预防 阻力的进一步出现。