Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, Russia.
Department of Chemistry, Faculty of Bioengineering and Bioinformatics and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
Nat Chem Biol. 2020 Oct;16(10):1071-1077. doi: 10.1038/s41589-020-0578-x. Epub 2020 Jun 29.
The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously thought. Despite the structural similarity to the well-known translation inhibitor tetracycline, we show that TcmX does not interact with the small ribosomal subunit, but rather binds to the large subunit, within the polypeptide exit tunnel. This previously unappreciated binding site is located adjacent to the macrolide-binding site, where TcmX stacks on the noncanonical basepair formed by U1782 and U2586 of the 23S ribosomal RNA. Although the binding site is distinct from the macrolide antibiotics, our results indicate that like macrolides, TcmX allows translation of short oligopeptides before further translation is blocked.
耐药性病原菌的增加使得我们目前临床使用的抗生素变得过时，这凸显了迫切需要具有独特靶标结合位点的新先导化合物来避免交叉耐药性。在这里，我们报告芳香聚酮类抗生素四烯霉素（TcmX）是一种有效的蛋白质合成抑制剂，不像之前认为的那样会诱导 DNA 损伤。尽管 TcmX 的结构与著名的翻译抑制剂四环素相似，但我们发现它不与小核糖体亚基相互作用，而是与大亚基结合，位于多肽出口隧道内。这个以前未被认识到的结合位点位于大环内酯结合位点附近，TcmX 堆积在由 23S 核糖体 RNA 的 U1782 和 U2586 形成的非典型碱基对上。尽管结合位点与大环内酯类抗生素不同，但我们的结果表明，与大环内酯类抗生素一样，TcmX 允许在进一步翻译受阻之前翻译短的寡肽。
