Salt-resistant homodimeric bactenecin, a cathelicidin-derived antimicrobial peptide.
The cathelicidin antimicrobial peptide bactenecin is a beta-hairpin molecule with a single disulfide bond and broad antimicrobial activity. The proform of bactenecin exists as a dimer, however, and it has been proposed that bactenecin is released as a dimer in vivo, although there has been little study of the dimeric form of bactenecin. To investigate the effect of bactenecin dimerization on its biological activity, we characterized the dimer's effect on phospholipid membranes, the kinetics of its bactericidal activity, and its salt sensitivity. We initially synthesized two bactenecin dimers (antiparallel and parallel) and two monomers (beta-hairpin and linear). Under oxidative folding conditions, reduced linear bactenecin preferentially folded into a dimer forming a ladder-like structure via intermolecular disulfide bonding. As compared to the monomer, the dimer had a greater ability to induce lysis of lipid bilayers and was more rapidly bactericidal. Interestingly, the dimer retained antimicrobial activity at physiological salt concentrations (150 mm NaCl), although the monomer was inactivated. This salt resistance was also seen with bactenecin dimer containing one intermolecular disulfide bond, and the bactenecin dimer appears to undergo multimeric oligomerization at high salt concentrations. Overall, dimeric bactenecin shows potent and rapid antimicrobial activity, and resists salt-induced inactivation under physiological conditions through condensation and oligomerization. These characteristics shed light on the features that a peptide would need to serve as an effective therapeutic agent.
Lee
Ju Y
JY
Department of Life Science, BioImaging Research Center, Gwangju Institute of Science and Technology, Korea.
Yang
Sung-Tae
ST
Lee
Seung K
SK
Jung
Hyun H
HH
Shin
Song Y
SY
Hahm
Kyung-Soo
KS
Kim
Jae I
JI
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002942:Circular Dichroism; D019281:Dimerization; D006461:Hemolysis / Q000187:drug effects; D007700:Kinetics; D008081:Liposomes; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D012965:Sodium Chloride / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D008081:Liposomes; D010456:Peptides, Cyclic; C056454:bactenecin; D012965:Sodium Chloride