Lun Shichun, Xiao Shiqi, Zhang Wei, Wang Shuangshuang, Gunosewoyo Hendra, Yu Li-Fang, Bishai William R
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, and Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
Antimicrob Agents Chemother. 2023 May 1;95(5). doi: 10.1128/AAC.02190-20. Epub 2021 Feb 8.
Polyketide synthase 13 (Pks13) is an important enzyme found in () that condenses two fatty acyl chains to produce α-alkyl β-ketoesters, which in turn serve as the precursors for the synthesis of mycolic acids that are essential building blocks for maintaining the cell wall integrity of Coumestan derivatives have recently been identified in our group as a new chemotype that exert their antitubercular effects via targeting of Pks13. These compounds were active on both drug-susceptible and drug-resistant strains of as well as showing low cytotoxicity to healthy cells and a promising selectivity profile. No cross-resistance was found between the coumestan derivatives and first-line TB drugs. Here we report that treatment of bacilli with 15 times the MIC of compound , an optimized lead coumestan compound, resulted in a colony forming unit (CFU) reduction from 6.0 log units to below the limit of detection (1.0 log units) per mL culture, demonstrating a bactericidal mechanism of action. Single dose (10 mg/kg) pharmacokinetic studies revealed favorable parameters with a relative bioavailability of 19.4%. In a mouse infection and chemotherapy model, treatment with showed dose-dependent mono-therapeutic activity, whereas treatment with in combination with rifampin showed clear synergistic effects. Together these data suggest that coumestan derivatives are promising agents for further TB drug development.
聚酮合酶13（Pks13）是一种在（）中发现的重要酶，它能缩合两条脂肪酰链以产生α-烷基β-酮酯，而α-烷基β-酮酯又作为合成分枝菌酸的前体，分枝菌酸是维持（）细胞壁完整性的重要组成部分。香豆雌酚衍生物最近在我们小组中被鉴定为一种新的化学类型，它通过靶向Pks13发挥抗结核作用。这些化合物对结核分枝杆菌的药物敏感株和耐药株均有活性，对健康细胞的细胞毒性较低，且具有良好的选择性。香豆雌酚衍生物与一线抗结核药物之间未发现交叉耐药性。在此我们报告，用优化的先导香豆雌酚化合物（化合物）的15倍最低抑菌浓度处理结核杆菌，导致每毫升培养物中的菌落形成单位（CFU）从6.0对数单位降至检测限以下（1.0对数单位），证明了其杀菌作用机制。单剂量（10 mg/kg）药代动力学研究显示出良好的参数，相对生物利用度为19.4%。在小鼠感染和化疗模型中，（化合物）治疗显示出剂量依赖性的单药治疗活性，而（化合物）与利福平联合治疗显示出明显的协同作用。这些数据共同表明，香豆雌酚衍生物是进一步开发抗结核药物的有前景的药物。
