Improved bioactivity of antimicrobial peptides by addition of amino-terminal copper and nickel (ATCUN) binding motifs

ChemMedChem. 2014 Aug;9(8):1892-901. doi: 10.1002/cmdc.201402033. Epub 2014 May 6.

Abstract

Antimicrobial peptides (AMPs) are promising candidates to help circumvent antibiotic resistance, which is an increasing clinical problem. Amino-terminal copper and nickel (ATCUN) binding motifs are known to actively form reactive oxygen species (ROS) upon metal binding. The combination of these two peptidic constructs could lead to a novel class of dual-acting antimicrobial agents. To test this hypothesis, a set of ATCUN binding motifs were screened for their ability to induce ROS formation, and the most potent were then used to modify AMPs with different modes of action. ATCUN binding motif-containing derivatives of anoplin (GLLKRIKTLL-NH2), pro-apoptotic peptide (PAP; KLAKLAKKLAKLAK-NH2), and sh-buforin (RAGLQFPVGRVHRLLRK-NH2) were synthesized and found to be more active than the parent AMPs against a panel of clinically relevant bacteria. The lower minimum inhibitory concentration (MIC) values for the ATCUN-anoplin peptides are attributed to the higher pore-forming activity along with their ability to cause ROS-induced membrane damage. The addition of the ATCUN motifs to PAP also increases its ability to disrupt membranes. DNA damage is the major contributor to the activity of the ATCUN-sh-buforin peptides. Our findings indicate that the addition of ATCUN motifs to AMPs is a simple strategy that leads to AMPs with higher antibacterial activity and possibly to more potent, usable antibacterial agents.

Keywords: amino-terminal copper & nickel (ATCUN) binding motifs; antimicrobial peptides; bioinorganic chemistry; cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / metabolism
  • Anti-Infective Agents / pharmacology*
  • Antimicrobial Cationic Peptides* / chemistry
  • Antimicrobial Cationic Peptides* / pharmacology
  • Copper / chemistry*
  • Copper / metabolism
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / metabolism
  • Gram-Positive Bacteria / drug effects*
  • Gram-Positive Bacteria / metabolism
  • Nickel / chemistry*
  • Nickel / metabolism
  • Peptide Library
  • Protein Binding
  • Protein Structure, Secondary
  • Reactive Oxygen Species / metabolism

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Peptide Library
  • Reactive Oxygen Species
  • Copper
  • Nickel