title: Structure-Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, FR 3631, Institut de Biologie Paris Seine (IBPS), Biogenèse des Signaux Peptidiques (BIOSIPE), F-75005 Paris, France.|CNRS, FR 3631, IBPS, BIOSIPE, F-75005, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: André
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Washington
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Darby
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Marvin M
authors.initials: MM
authors.lastname: Vega
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Ari D
authors.initials: AD
authors.lastname: Filip
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Ash
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Katy A
authors.initials: KA
authors.lastname: Muzikar
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Piesse
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, FR 3631, Institut de Biologie Paris Seine (IBPS), Biogenèse des Signaux Peptidiques (BIOSIPE), F-75005 Paris, France.|CNRS, FR 3631, IBPS, BIOSIPE, F-75005, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Foulon
authors.affiliation: Department of Chemistry, Pomona College , 645 N College Avenue, Claremont, California 91711, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Leary
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, FR 3631, Institut de Biologie Paris Seine (IBPS), Biogenèse des Signaux Peptidiques (BIOSIPE), F-75005 Paris, France.|CNRS, FR 3631, IBPS, BIOSIPE, F-75005, Paris, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Ladram
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D002460:Cell Line; D002942:Circular Dichroism; D004926:Escherichia coli / Q000187:drug effects*; D014644:Genetic Variation; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D011506:Proteins; C104501:temporin