Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

ACS Infect Dis. 2023 Jan 13;9(1):111-121. doi: 10.1021/acsinfecdis.2c00446. Epub 2022 Dec 15.

Abstract

Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide's biosynthesis, stability, and bioactivity.

Keywords: Enterobacter cloacae; RiPPs; antimicrobial lasso peptide; carbapenem-resistant Enterobacterales; cloacaenodin; genome mining.

MeSH terms

  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Antimicrobial Peptides
  • Carbapenems
  • Enterobacter* / genetics
  • Peptides / chemistry
  • Peptides / pharmacology

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Peptides
  • Carbapenems
  • Peptides