Discovery of Peptide Antibiotics Composed of d-Amino Acids

ACS Chem Biol. 2019 Jul 19;14(7):1498-1506. doi: 10.1021/acschembio.9b00234. Epub 2019 Jun 21.

Abstract

A paucity of viable programs and pipelines for the discovery of new antibiotics poses a significant public health threat. The emergence of resistant strains against vancomycin is particularly dangerous in hospital settings. Here, we report the design of enantiomeric targets based on bacterial cell wall biosynthesis precursors that allow for selection and identification of short linear, cyclic and bicyclic peptides that are composed of d-amino acids. These compounds are active against Staphylococcus aureus, Methicillin-resistant S. aureus, and vancomycin-resistant Enterococci that possess moderately high antibacterial activity and furthermore display no toxicity to both human red blood cells and mammalian cells at these concentrations. This 'mirror image phage display' approach yielded templates that can serve as scaffolds for further improvements in activity-based structural modifications. This strategy has the potential to provide a new class of antimicrobials that are metabolically stable and have the promise for oral delivery. The use of this platform combined with traditional medicinal chemistry approaches could rapidly yield large numbers of new therapeutic lead compounds.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry*
  • Amino Acids / pharmacology*
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemistry*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Drug Discovery
  • Enterococcus / drug effects
  • Erythrocytes / drug effects
  • HeLa Cells
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Peptide Library
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Vancomycin Resistance

Substances

  • Amino Acids
  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Peptide Library