An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance

Science. 2024 Feb 16;383(6684):721-726. doi: 10.1126/science.adk8013. Epub 2024 Feb 15.


We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Bridged-Ring Compounds* / chemical synthesis
  • Bridged-Ring Compounds* / chemistry
  • Bridged-Ring Compounds* / pharmacology
  • Drug Design
  • Drug Resistance, Multiple, Bacterial*
  • Erythromycin / chemistry
  • Erythromycin / pharmacology
  • Escherichia coli / drug effects
  • Lincosamides* / chemical synthesis
  • Lincosamides* / chemistry
  • Lincosamides* / pharmacology
  • Mice
  • Microbial Sensitivity Tests
  • Oxepins* / chemical synthesis
  • Oxepins* / chemistry
  • Oxepins* / pharmacology
  • Pseudomonas aeruginosa / drug effects
  • Ribosomes / chemistry
  • Staphylococcus aureus / drug effects


  • Anti-Bacterial Agents
  • Erythromycin
  • cresomycin
  • Bridged-Ring Compounds
  • Oxepins
  • Lincosamides