Structure-Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity

  • ACS Chem Biol. 2015 Oct 16;10(10):2257-66. doi: 10.1021/acschembio.5b00495.
Sonia André  1  2 ,  Shannon K Washington  3 ,  Emily Darby  3 ,  Marvin M Vega  3 ,  Ari D Filip  3 ,  Nathaniel S Ash  3 ,  Katy A Muzikar  3 ,  Christophe Piesse  4 ,  Thierry Foulon  1  2 ,  Daniel J O'Leary  3 ,  Ali Ladram  1  2
Affiliations
  • 1. Sorbonne Universités, UPMC Univ Paris 06, FR 3631, Institut de Biologie Paris Seine (IBPS), Biogenèse des Signaux Peptidiques (BIOSIPE), F-75005 Paris, France.
  • 2. CNRS, FR 3631, IBPS, BIOSIPE, F-75005, Paris, France.
  • 3. Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
  • 4. Sorbonne Universités, UPMC Univ Paris 06, FR 3631, Institut de Biologie Paris Seine (IBPS), Plate-forme Ingénierie des Protéines et Synthèse Peptidique, F-75005 Paris, France.
PMID: 26181487 DOI: 10.1021/acschembio.5b00495
Abstract

Short antimicrobial peptides represent attractive compounds for the development of new Antibiotic agents. Previously, we identified an ultrashort hydrophobic and phenylalanine-rich peptide, called temporin-SHf, representing the smallest natural amphibian antimicrobial peptide known to date. Here, we report on the first structure-activity relationship study of this peptide. A series of temporin-SHf derivatives containing insertion of a basic arginine residue as well as residues containing neutral hydrophilic (serine and α-hydroxymethylserine) and hydrophobic (α-methyl phenylalanine and p-(t)butyl phenylalanine) groups were designed to improve the antimicrobial activity, and their α-helical structure was investigated by circular dichroism and nuclear magnetic resonance spectroscopy. Three compounds were found to display higher antimicrobial activity with the ability to disrupt (permeabilization/depolarization) the Bacterial membrane while retaining the nontoxic character of the parent peptide toward rat erythrocytes and human cells (THP-1 derived macrophages and HEK-293). Antimicrobial assays were carried out to explore the influence of serum and physiological salt concentration on peptide activity. Analogs containing d-amino acid residues were also tested. Our study revealed that [p-(t)BuF(2), R(5)]SHf is an attractive ultrashort candidate that is highly potent (bactericidal) against Gram-positive bacteria (including multidrug resistant S. aureus) and against a wider range of clinically interesting Gram-negative bacteria than temporin-SHf, and also active at physiological salt concentrations and in 30% serum.

Products