Stapled Phd Peptides Inhibit Doc Toxin Induced Growth Arrest in Salmonella

ACS Chem Biol. 2023 Dec 15;18(12):2485-2494. doi: 10.1021/acschembio.3c00411. Epub 2023 Nov 21.

Abstract

Bacterial toxin inhibition is a promising approach to overcoming antibiotic failure. InSalmonella, knockout of the toxin Doc has been shown to significantly reduce the formation of antibiotic-tolerant persisters. Doc is a kinase that is inhibited in nontolerant cells by its cognate antitoxin, Phd. In this work, we have developed first-in-class stapled peptide antitoxin mimetics based on the Doc inhibitory sequence of Phd. After making a series of substitutions to improve bacterial uptake, we identified a lead stapled Phd peptide that is able to counteract Doc toxicity in Salmonella. This provides an exciting starting point for the further development of therapeutic peptides capable of reducing antibiotic persistence in pathogenic bacteria.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Antitoxins*
  • Bacterial Proteins
  • Bacterial Toxins*
  • Peptides / pharmacology
  • Salmonella

Substances

  • Bacterial Toxins
  • Antitoxins
  • Peptides
  • Anti-Bacterial Agents
  • Bacterial Proteins