Identification of Synthetic Host Defense Peptide Mimics That Exert Dual Antimicrobial and Anti-Inflammatory Activities

Abstract

ABSTRACTA group of synthetic antimicrobial oligomers, inspired by naturally occurring antimicrobial peptides, were analyzed for the ability to modulate innate immune responses to Toll-like receptor (TLR) ligands. These synthetic mimics of antimicrobial peptides (SMAMPs) specifically reduced cytokine production in response toStaphylococcus aureusand theS. aureuscomponent lipoteichoic acid (LTA), a TLR2 agonist. Anti-inflammatory SMAMPs prevented the induction of tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-10 in response toS. aureusor LTA, but no other TLR2 ligands. We show that these SMAMPs bind specifically to LTAin vitroand prevent its interaction with TLR2. Importantly, the SMAMP greatly reduced the induction of TNF and IL-6in vivoin mice acutely infected withS. aureuswhile simultaneously reducing bacterial loads dramatically (4 log10). Thus, these SMAMPs can eliminate the damage induced by pathogen-associated molecular patterns (PAMPs) while simultaneously eliminating infectionin vivo. They are the first known SMAMPs to demonstrate anti-inflammatory and antibacterial activitiesin vivo.