Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling

Nature. 2020 Feb;578(7796):582-587. doi: 10.1038/s41586-020-1990-9. Epub 2020 Feb 12.


Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections1. Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family2. Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter2. Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics-the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin-that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins-essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.

MeSH terms

  • Actinobacteria / chemistry
  • Actinobacteria / genetics
  • Actinobacteria / metabolism
  • Animals
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / metabolism
  • Anti-Bacterial Agents* / pharmacology
  • Biosynthetic Pathways / genetics
  • Cell Wall / metabolism
  • Chlorophenols / chemistry
  • Chlorophenols / metabolism
  • Chlorophenols / pharmacology
  • Disease Models, Animal
  • Drug Discovery*
  • Drug Resistance, Microbial / drug effects
  • Drug Resistance, Microbial / genetics
  • Female
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • Multigene Family
  • N-Acetylmuramoyl-L-alanine Amidase / antagonists & inhibitors
  • Peptides, Cyclic* / chemistry
  • Peptides, Cyclic* / metabolism
  • Peptides, Cyclic* / pharmacology
  • Peptidoglycan / drug effects*
  • Peptidoglycan / metabolism*
  • Phylogeny
  • Skin / microbiology
  • Staphylococcal Infections / microbiology


  • Anti-Bacterial Agents
  • Chlorophenols
  • Peptides, Cyclic
  • Peptidoglycan
  • corbomycin
  • complestatin
  • N-Acetylmuramoyl-L-alanine Amidase