Wu Kelvin J Y, Aleksandrova Elena V, Robinson Paul J, Benedetto Amy E, Yu Meiyi, Tresco Ben I C, See Dominic N Y, Jiang Tong, Ramkissoon Antonio, Dunand Clémence F, Svetlov Maxim S, Lee Joonho, Polikanov Yury S, Myers Andrew G
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
These authors contributed equally.
Chem. 2025 Jul 10;11(7). doi: 10.1016/j.chempr.2025.102480. Epub 2025 Mar 7.
We recently reported the conception and synthesis of cresomycin (), a fully synthetic lincosamide antibiotic effective in vitro and in vivo against multidrug-resistant Gram-positive and Gram-negative bacteria. In this work, we describe the chemical synthesis and characterization of sulfur atom replacement analogs (S → CH), (S → O), and (S → Se). Comparison of high-resolution co-crystal structures showed that the four analogs adopted identical conformations when bound to the bacterial ribosome, but due to variations of ≤1 Å in the bond lengths between the anomeric carbon and the varied atoms, only the and heteroatoms of and , respectively, were positioned to interact with the π-face of nucleobase G2505. and did not benefit from such stabilizations, with correspondingly negative consequences in both target engagement and antibacterial activities. We therefore conclude that the sulfur atom of the lincosamides is important in ribosomal binding.
我们最近报道了新月霉素（）的构想与合成，它是一种全合成林可酰胺类抗生素，在体外和体内对多重耐药革兰氏阳性菌和革兰氏阴性菌均有效。在这项工作中，我们描述了硫原子取代类似物（S → CH）、（S → O）和（S → Se）的化学合成及表征。高分辨率共晶体结构比较表明，这四种类似物与细菌核糖体结合时采取相同构象，但由于端基碳与不同原子之间的键长变化≤1 Å，只有和中的和杂原子分别定位为与核碱基G2505的π面相互作用。和未从这种稳定作用中受益，在靶点结合和抗菌活性方面都产生了相应的负面后果。因此，我们得出结论，林可酰胺类的硫原子在核糖体结合中很重要。
