Bactericidal activity of mammalian cathelicidin-derived peptides

Endogenous antimicrobial peptides of the cathelicidin family contribute to innate immunity. The emergence of widespread antibiotic resistance in many commonly encountered bacteria requires the search for new bactericidal. age nts with therapeutic potential, Solid-phase synthesis was employed to prepa re linear antimicrobial peptides found in cathelicidins of five mammals: hu man (FALL39/LL37), rabbit (CAP18), mouse (mCRAMP), rat (rCRAMP), and sheep (SMAP29 and SMAP34). These peptides were tested at ionic strengths of 25 an d 175 nM against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus a ureus, and methicillin-resistant Staphylococcus aureus. Each peptide manife sted activity against P. aeruginosa irrespective of the NaCl concentration. CAP18 and SMAP29 were the most effective peptides of the group against all test organisms under both lan and high-salt conditions. Select peptides of 15 to 21 residues, modeled on CAP18 (37 residues), retained activity again st the gram-negative bacteria and methicillin-sensitive S. aureus, although the bactericidal activity was reduced compared to that of the parent pepti de. In accordance with the behavior of the parent molecule, the truncated p eptides adopted an alpha-helical structure in the presence of trifluoroetha nol or lipopolysaccharide. The relationship between the bactericidal activi ty and several physiochemical properties of the cathelicidins was examined. The activities of the full-length peptides correlated positively with a pr edicted gradient of hydrophobicity along the peptide backbone and with net positive charge; they correlated inversely with relative abundance of anion ic residues. The salt-resistant, antimicrobial properties of CAP18 and SMAP 29 suggest that these peptides or congeneric structures have potential for the treatment of bacterial infections in normal and immunocompromised perso ns and individuals with cystic fibrosis.