Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides

Nat Microbiol. 2018 Jun;3(6):718-731. doi: 10.1038/s41564-018-0164-0. Epub 2018 May 24.


Antimicrobial peptides are promising alternative antimicrobial agents. However, little is known about whether resistance to small-molecule antibiotics leads to cross-resistance (decreased sensitivity) or collateral sensitivity (increased sensitivity) to antimicrobial peptides. We systematically addressed this question by studying the susceptibilities of a comprehensive set of 60 antibiotic-resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic-resistant bacteria show a high frequency of collateral sensitivity to antimicrobial peptides, whereas cross-resistance is relatively rare. We identify clinically relevant multidrug-resistance mutations that increase bacterial sensitivity to antimicrobial peptides. Collateral sensitivity in multidrug-resistant bacteria arises partly through regulatory changes shaping the lipopolysaccharide composition of the bacterial outer membrane. These advances allow the identification of antimicrobial peptide-antibiotic combinations that enhance antibiotic activity against multidrug-resistant bacteria and slow down de novo evolution of resistance. In particular, when co-administered as an adjuvant, the antimicrobial peptide glycine-leucine-amide caused up to 30-fold decrease in the antibiotic resistance level of resistant bacteria. Our work provides guidelines for the development of efficient peptide-based therapies of antibiotic-resistant infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Bacterial Outer Membrane Proteins / genetics
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Synergism
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / growth & development*
  • Escherichia coli Proteins / genetics
  • Microbial Sensitivity Tests
  • Mutation
  • Small Molecule Libraries / pharmacology


  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Outer Membrane Proteins
  • Escherichia coli Proteins
  • Small Molecule Libraries
  • peptide-Gly-Leu-amide