State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, 510530, China.
Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.
Nat Commun. 2019 Jan 31;10(1):524. doi: 10.1038/s41467-019-08464-y.
Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.
布鲁里溃疡（BU）是一种新兴的传染病，可导致毁容性皮肤溃疡。病原体溃疡分枝杆菌分泌一种称为(mycolactone)的毒素，引发炎症和免疫病理学反应。现有的治疗方法漫长而复杂，且使用的药物是为结核病开发的。在这里，我们报告说，一种吡唑并[1,5-a]吡啶-3-甲酰胺（TB47）对溃疡分枝杆菌具有高度杀菌作用，无论是在体外还是体内。在经过验证的 BU 小鼠模型中，与世界卫生组织推荐的标准 BU 治疗方案相比，TB47 单独使用可使小鼠脚垫中的溃疡分枝杆菌负荷减少 2.5 个对数 CFU 以上。我们表明，泛醌-细胞色素 C 还原酶细胞色素亚基 B 的突变赋予了 TB47 耐药性，并且不同分枝杆菌的 CydABs 的不相似性可能解释了它们对 TB47 的敏感性差异。TB47 对溃疡分枝杆菌具有高度活性，具有理想的药理学特性和低毒性，这使其成为治疗 BU 的进一步评估的候选药物。
