State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, 610041, Sichuan, China.
Sci Rep. 2016 Jul 13;6:29717. doi: 10.1038/srep29717.
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.
需要新的化疗化合物来对抗耐多药结核分枝杆菌（Mtb），这仍然是一个严重的公共卫生挑战。去甲二氢愈创木酸磷酸-β-D-核糖 2'-差向异构酶（DprE1 酶）已被确定为解决这一紧迫需求的有吸引力的治疗靶点。在此，我们发现了一类新的 DprE1 抑制剂苯并噻嗪硫酮类化合物作为抗结核药物。苯并噻嗪硫酮类似物 SKLB-TB1001 在微量 Alamar 蓝测定和细胞内模型中对 Mtb 表现出优异的活性，同时 SKLB-TB1001 对多药耐药广泛耐药和耐药临床分离株也具有很高的活性。重要的是，在本研究中测试的任何两种药物组合都没有发现拮抗相互作用，并且 SKLB-TB1001 与利福平（RMP）的组合被证明是协同的。此外，苯并噻嗪硫酮在急性 Mtb 感染小鼠模型中表现出出色的体内抗结核疗效，明显优于 BTZ043。这些数据结合苯并噻嗪硫酮的生物利用度和安全性概况表明，SKLB-TB1001 是一种有前途的治疗耐药结核病的临床前候选药物。
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