A fowlicidin-1 analog protects mice from lethal infections induced by methicillin-resistant Staphylococcus aureus.
Fowlicidin-1 is a newly identified alpha-helical cathelicidin host defense peptide. We have shown that fowlicidin-1 possesses potent antibacterial activity, but also displays considerable toxicity toward mammalian cells. To further identify fowlicidin-1 analog(s) with enhanced therapeutic potential, a series of amino-terminal truncation analogs were synthesized and functionally evaluated. Relative to the full-length peptide, fowl-1(6-26), an analog with omission of five amino-terminal amino acid residues, maintained the antibacterial potency against a range of Gram-negative and Gram-positive bacteria including antibiotic-resistant strains. Fowl-1(6-26)-NH(2), a carboxyl-terminal amidated form of fowl-1(6-26), retained the antibacterial activity for a minimum of 2h in the presence of 100% serum. In addition, an intraperitoneal administration of 10mg/kg of fowl-1(6-26)-NH(2) led to a 50% increase in the survival of neutropenic mice over a 7-day period from a lethal dose of methicillin-resistant Staphylococcus aureus (MRSA), concomitant with a reduction in the bacterial titer in both peritoneal fluids and spleens of mice 24h post-infection. Fowl-1(6-26)-NH(2) at 20 microM was further found to suppress lipopolysaccharide-mediated production of TNF-alpha and nitric oxide in macrophages by 77% and 96%, respectively. Therefore, with potent endotoxin-neutralizing and bactericidal activities, fowlicidin-1(6-26)-NH(2), may have strong therapeutic potential for drug-resistant infections and sepsis.
Bommineni
Yugendar R
YR
Department of Animal Science, Oklahoma State University, Stillwater, OK 74078, USA.
Achanta
Mallika
M
Alexander
Justin
J
Sunkara
Lakshmi T
LT
Ritchey
Jerry W
JW
Zhang
Guolong
G
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D054804:Cathelicidins / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000517:prevention & control*
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D010446:Peptide Fragments; C000588755:fowlicidin-1(6-26)