Many small-molecule antibiotics function by disrupting bacterial ribosomes, but bacteria develop resistance by modifying ribosomes to reduce the binding affinity of these molecules. Writing in Science, Wu et al. present a solution to this challenge by engineering a synthetic antibiotic that remains locked in an optimal conformation that boosts ribosomal binding.

The authors designed the molecule cresomycin on the basis of the structural analysis of ribosomes bound to clinically available lincosamide antibiotics. Lincosamides can be separated into two fragments by hydrolysis, and scaffolds can then be added to conformationally restrict them. Previous work identified a scaffold that improved the antibiotic potency of lincosamides. The authors optimized the antibiotic potency of ribosome-targeting molecules by exploring other scaffolds that further rigidify their shape. Computational, structural and biochemical experiments showed that cresomycin contains a previously unexplored scaffold that locks the molecule in the exact conformation required for effective binding.

许多小分子抗生素通过破坏细菌核糖体发挥作用，但细菌通过修饰核糖体以降低这些分子的结合亲和力而产生耐药性。吴等人在《科学》上写作。通过设计一种合成抗生素来解决这一挑战，该抗生素保持锁定在增强核糖体结合的最佳构象。

作者根据与临床可用的林可酰胺抗生素结合的核糖体的结构分析，设计了克雷霉素分子。林可酰胺可以通过水解分成两个片段，然后可以添加支架以在构象上限制它们。先前的工作确定了一种可以提高林可酰胺抗生素效力的支架。作者通过探索其他进一步硬化核糖体靶向分子形状的支架，优化了核糖体靶向分子的抗生素效力。计算、结构和生化实验表明，cresomycin 含有一种先前未开发的支架，可将分子锁定在有效结合所需的精确构象。