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.