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Structure–Activity Relationship-based Optimization of Small Temporin-SHf Analogs with Potent Antibacterial Activity
Version 2 2020-02-20, 11:43
Version 1 2016-02-12, 21:40
journal contribution
posted on 2020-02-20, 11:43 authored by Sonia André, Shannon K. Washington, Emily Darby, Marvin M. Vega, Ari D. Filip, Nathaniel
S. Ash, Katy A. Muzikar, Christophe Piesse, Thierry Foulon, Daniel J. O’Leary, Ali LadramShort 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-tbutyl 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-tBuF2, R5]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.