Clincelin: A redesigned lincosamide with enhanced intracellular accumulation and adaptive binding to resistant ribosomes

Lincosamides are an important class of clinically used antibiotics that inhibit translation by binding to the peptidyl transferase center of the ribosome. However, their efficacy is impaired by the widespread acquisition of genes coding for erythromycin resistance methyltransferase (Erm), which confer resistance by dimethylating adenine A2058 in the 23S ribosomal RNA. Here, we report clincelin, a novel chimeric lincosamide that retains conserved lincosamide thiooctose core and integrates structural features from two natural antibiotics—a propylated proline from lincomycin and salicylate from celesticetin—together with additional clinically validated C7 chlorination. Biochemical and cellular analyses revealed that the presence of salicylate and chlorination synergistically enhances intracellular accumulation, giving clincelin greater antibacterial activity than the parent compounds and the clinically used clindamycin. Notably, clincelin partially retains its efficacy against erm -mediated resistant pathogens, which is explained by cryo-electron microscopy showing that the salicylate moiety adopts distinct binding modes on drug-sensitive versus A2058-dimethylated Staphylococcus aureus ribosomes. Altogether, a comprehensive functional understanding of lincosamide structural modifications will enable the development of novel agents designed to overcome existing resistance.