Temporal shifts in antibiotic resistance elements govern phage-pathogen conflicts

Science. 2021 Jul 30;373(6554):eabg2166. doi: 10.1126/science.abg2166.


Bacteriophage predation selects for diverse antiphage systems that frequently cluster on mobilizable defense islands in bacterial genomes. However, molecular insight into the reciprocal dynamics of phage-bacterial adaptations in nature is lacking, particularly in clinical contexts where there is need to inform phage therapy efforts and to understand how phages drive pathogen evolution. Using time-shift experiments, we uncovered fluctuations in Vibrio cholerae's resistance to phages in clinical samples. We mapped phage resistance determinants to SXT integrative and conjugative elements (ICEs), which notoriously also confer antibiotic resistance. We found that SXT ICEs, which are widespread in γ-proteobacteria, invariably encode phage defense systems localized to a single hotspot of genetic exchange. We identified mechanisms that allow phage to counter SXT-mediated defense in clinical samples, and document the selection of a novel phage-encoded defense inhibitor. Phage infection stimulates high-frequency SXT ICE conjugation, leading to the concurrent dissemination of phage and antibiotic resistances.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacteriolysis
  • Cholera / microbiology
  • Conjugation, Genetic
  • Drug Resistance, Bacterial / genetics*
  • Epigenesis, Genetic
  • Feces / microbiology
  • Feces / virology
  • Gammaproteobacteria / genetics
  • Gammaproteobacteria / virology
  • Genes, Bacterial
  • Genes, Viral
  • Genome, Bacterial
  • Genome, Viral
  • Host Specificity
  • Humans
  • Interspersed Repetitive Sequences*
  • Microbial Interactions
  • Myoviridae / genetics
  • Myoviridae / isolation & purification
  • Myoviridae / physiology*
  • Vibrio cholerae / drug effects*
  • Vibrio cholerae / genetics
  • Vibrio cholerae / isolation & purification
  • Vibrio cholerae / virology*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism


  • Viral Proteins