Microbiology：抑制IMPDH酶功能可杀死结核杆菌

　　英国研究人员日前报告说，有些化合物可以通过抑制结核杆菌中一种酶的功能来杀死这种细菌，这是一种对付结核杆菌的新方法，将有助于研发治疗肺结核的新药物。

　　英国伯明翰大学等机构研究人员在新一期《微生物学》杂志上报告说，结核杆菌中一种名为IMPDH的酶对细菌细胞的生存至关重要，抑制这种酶的功能就可以杀死结核杆菌。研究人员测试了多种相关化合物，发现有3种二苯脲类化合物抑制这种酶的效率都在90％以上。

　　研究人员说，这种酶对人类细胞和细菌细胞都很重要，在治疗人类癌症的实践中，已经将它作为药物靶点来杀灭癌细胞。而且，本次研究测试的几种化合物都是“选择性活跃”，它们只对结核杆菌中的这种酶有效，而不会杀死正常的人体细胞，因此可以在此基础上研发新的治疗肺结核的药物。

　　结核杆菌是引起肺结核等疾病的病原菌。肺结核曾长期被认为是不治之症，后来一些抗生素问世后，肺结核的治疗变得较为容易。但近年来结核杆菌对已有药物的耐药性逐渐增强，世界卫生组织也警告说，肺结核在全球有卷土重来的趋势，因此研究人员一直在致力寻找治疗肺结核的新方法。

　　推荐英文摘要：

　　Microbiology DOI：10.1099/mic.0.042549-0

　　Identification of novel diphenyl urea inhibitors of Mt-Guab2 active against Mycobacterium tuberculosis

　　Veeraraghavan Usha1, Sudagar S Gurcha1, Andrew Lovering1, Adrian J Lloyd2, Athina Papaemmanouil1, Robert C Reynolds3 and Gurdyal S Besra1,4

　　1 University of Birmingham;

　　2 University of Warwick;

　　3 Southern Research Insititute

　　In contrast to most bacteria which harbor a single inosine monophosphate dehydrogenase (IMPDH) gene, the genomic sequence of Mycobacterium tuberculosis H37Rv predicts three genes encoding IMPDH: guab1, guab2 and guab3. The three genes encoding IMPDH from M. tuberculosis H37Rv were cloned and expressed in Escherichia coli to evaluate functional IMPDH activity. Purified recombinant Mt-Guab2 which uses inosine monophosphate (IMP) as a substrate was identified as the only active Guab ortholog in M. tuberculosis and was optimal at pH 8.5 and 37 °C. Mt-Guab2 was inhibited significantly in vitro by a panel of diphenyl urea-based derivatives, which were also potent anti-mycobacterial agents against M. tuberculosis and Mycobacterium smegmatis with minimum inhibitory concentrations (MICs) in the range of 0.2 to 0.5 μg ml-1. When Mt-Guab2 was over-expressed on a plasmid in trans in M. smegmatis, a diphenyl urea analogue showed a 16-fold increase in MIC. Interestingly, when Mt-Guab orthologs (Mt-Guab1 and 3) were also overexpressed on a plasmid in trans in M. smegmatis they also conferred resistance, suggesting that although these Mt-guab orthologs were inactive in vitro they presumably titrate the effect of the inhibitory properties of the active compounds in vivo.