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.