title: Identification of synthetic host defense peptide mimics that exert dual antimicrobial and anti-inflammatory activities.
abstract: A 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 to Staphylococcus aureus and the S. aureus component 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 to S. aureus or LTA, but no other TLR2 ligands. We show that these SMAMPs bind specifically to LTA in vitro and prevent its interaction with TLR2. Importantly, the SMAMP greatly reduced the induction of TNF and IL-6 in vivo in mice acutely infected with S. aureus while simultaneously reducing bacterial loads dramatically (4 log(10)). Thus, these SMAMPs can eliminate the damage induced by pathogen-associated molecular patterns (PAMPs) while simultaneously eliminating infection in vivo. They are the first known SMAMPs to demonstrate anti-inflammatory and antibacterial activities in vivo.
authors.affiliation: Department of Polymer Science and Engineering, University of Massachusetts, Amherst, Massachusetts, USA.
authors.forename: Abhigyan
authors.initials: A
authors.lastname: Som
authors.forename: Nicolás
authors.initials: N
authors.lastname: Navasa
authors.forename: Avital
authors.initials: A
authors.lastname: Percher
authors.forename: Richard W
authors.initials: RW
authors.lastname: Scott
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Tew
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000302:isolation & purification*; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification*; D058491:Bacterial Load; D016207:Cytokines / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000235:genetics / Q000302:isolation & purification* / Q000494:pharmacology*; D011485:Protein Binding; D013203:Staphylococcal Infections / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology; D013682:Teichoic Acids / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D010455:Peptides; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid