Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity
Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity
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DOI：
10.1073/pnas.1302816110
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发表时间：
2013-06-18
影响因子：
11.1
通讯作者：
Keiler, Kenneth C.
中科院分区：
文献类型：
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作者：
Ramadoss, Nitya S.;Alumasa, John N.;Keiler, Kenneth C.
蛋白质标签和核糖体释放的反式翻译途径在广泛的病原体中对生存力和毒力起着关键作用，但在动物中没有发现。为了探索使用反式翻译作为抗生素开发的靶标，使用高通量筛选和二次筛选测定来鉴定该途径的小分子抑制剂。从筛选中回收抑制蛋白质标记和标记蛋白质的蛋白水解的化合物。最具活性的化合物之一KKL-35抑制反式翻译标记反应，IC 50 = 0.9 μ M。KKL-35和筛选中鉴定的其他化合物表现出广谱抗生素活性，验证了反式翻译作为药物开发的靶点。这种独特的靶标可以在对抗对现有抗生素具有耐药性的病原菌菌株方面发挥关键作用。
The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a high-throughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans-translation tagging reaction with an IC50 = 0.9 mu M. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics.