文章基本信息

标题：Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis
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作者：Chao Gao ; Cuiting Peng ; Yaojie Shi 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2016
卷号：6
期号：1
DOI：10.1038/srep29717
语种：English
出版社：Springer Nature
摘要：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.