PLoS ONE：多国科学家携手研究抗结核病新药

结核病是一种古老的疾病，其致死病例可以追溯到公元前3世纪，而目前每年还有大约140万人死于结核病。

结核分枝杆菌是结核病的病原体，常规化学药物治疗至少耗时6个月，且耐药现象日益严重。二氢叶酸还原酶催化产生的四氢叶酸是合成嘌呤和胸腺嘧啶的重要底物，抑制该酶的活性可以阻断DNA和RNA的合成，从而杀灭病原菌。

在世界卫生组织的支持下，中国、印度、肯尼亚、尼日利亚和美国的科研人员紧密合作，通过对结核分枝杆菌的二氢叶酸还原酶开展高通量筛选和相关药效学评价，发现了一个特异性抑制剂。该化合物不仅能够剂量依赖性阻断二氢叶酸还原酶的活性，而且可以抑制结核分枝杆菌的生长。这项阶段性研究成果近日已经发表在知名国际学刊PLoS ONE上（10.1371/journal.pone.0039961）。

卫生部部长陈竺向该合作项目的组织者、国家新药筛选中心主任王明伟研究员发来贺词：“这确实是一项振奋人心的进展！应该成为我们今后在全球卫生外交中开展合作的模式，即东-西合作和南-北联手并举，但以南—南合作为核心”。

世界卫生组织、卫生部（“重大新药创制”国家重大科技专项）、科技部、中国科学院和诺和诺德公司为该项研究提供了资助。

doi:10.1371/journal.pone.0039961
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High-throughput Screening and Sensitized Bacteria Identify an M. tuberculosis Dihydrofolate Reductase Inhibitor with Whole Cell Activity

Anuradha Kumar1#, Meng Zhang2#, Linyun Zhu2, Reiling P. Liao1, Charles Mutai2¤a, Shittu Hafsat2¤b, David R. Sherman1*, Ming-Wei Wang2*

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a bacterial pathogen that claims roughly 1.4 million lives every year. Current drug regimens are inefficient at clearing infection, requiring at least 6 months of chemotherapy, and resistance to existing agents is rising. There is an urgent need for new drugs that are more effective and faster acting. The folate pathway has been successfully targeted in other pathogens and diseases, but has not yielded a lead drug against tuberculosis. We developed a high-throughput screening assay against Mtb dihydrofolate reductase (DHFR), a critical enzyme in the folate pathway, and screened a library consisting of 32,000 synthetic and natural product-derived compounds. One potent inhibitor containing a quinazoline ring was identified. This compound was active against the wild-type laboratory strain H37Rv (MIC99 = 207 µM). In addition, an Mtb strain with artificially lowered DHFR levels showed increased sensitivity to this compound (MIC99 = 70.7 µM), supporting that the inhibition was target-specific. Our results demonstrate the potential to identify Mtb DHFR inhibitors with activity against whole cells, and indicate the power of using a recombinant strain of Mtb expressing lower levels of DHFR to facilitate the discovery of antimycobacterial agents. With these new tools, we highlight the folate pathway as a potential target for new drugs to combat the tuberculosis epidemic.