Division of Mycobacterial Research, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
Tuberculosis (Edinb). 2009 Sep;89(5):364-70. doi: 10.1016/j.tube.2009.07.002. Epub 2009 Aug 20.
Mycobacterium tuberculosis has an on-going impact on global public health and new therapeutics to treat tuberculosis are urgently required. The emergence of drug resistant tuberculosis poses a serious threat to the control of this pathogen, and the development of drugs that are active against the resistant strains is vital. A medium-throughput assay using the Alamar Blue reagent was set-up to identify novel inhibitors of M. tuberculosis from a library of known drugs, for which there has already been extensive research investigating their suitability and safety as human therapeutics. Of the 1514 compounds screened, 53 were demonstrated to possess inhibitory properties against M. tuberculosis at a concentration of 5microM or below. Of these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. It was demonstrated that all five were active against intracellular M. tuberculosis in a macrophage model of infection. The anti-tuberculosis agents identified in this screen represent promising new scaffolds on which future drug development efforts can be focused.
结核分枝杆菌对全球公共卫生持续产生影响，急需新的治疗结核病的药物。耐药结核病的出现对该病原体的控制构成严重威胁，因此开发对耐药菌株有效的药物至关重要。本研究建立了一种基于 Alamar Blue 试剂的高通量筛选方法，旨在从已广泛研究其作为人类治疗药物的适用性和安全性的已知药物库中鉴定结核分枝杆菌的新型抑制剂。在筛选的 1514 种化合物中，有 53 种在 5μM 或更低浓度下对结核分枝杆菌具有抑制作用。其中，有 17 种是新型抑制剂，而 36 种是已知的抗结核药物或先前被描述为具有抗结核活性的药物。选择了 5 种化合物作为最有希望的新抗结核药物的起始点。研究表明，这 5 种化合物在感染巨噬细胞模型中均对细胞内结核分枝杆菌具有活性。本研究中筛选出的抗结核药物代表了有前途的新骨架，未来的药物开发工作可以集中在这些骨架上。
