Conformation-dependent antibiotic activity of tritrpticin, a cathelicidin-derived antimicrobial peptide.
Tritrpticin, a Trp-rich cationic antimicrobial peptide with a unique amino acid sequence (VRRFPWWWPFLRR), is found in porcine cathelicidin cDNA. Tritrpticin has a broad spectrum of antibacterial and antifungal activities and hemolytic activity comparable to that of indolicidin. To investigate the mechanism of the bacterial killing action of tritrpticin and to identify structural features important for bacterial cell selectivity, we designed several tritrpticin analogs with amino acid substitutions of the Pro and Trp residues. Circular dichroism studies revealed that the substitution of Pro-->Ala (TPA) or Trp-->Phe (TWF) leads to significant conformational changes in SDS micelles, converting the beta-turn to alpha-helix or to poly-L-proline II helix, respectively. Compared to tritrpticin, TPA retained most of its antimicrobial activity, but showed enhanced hemolytic and membrane-disrupting activities. In contrast, TWF showed a 2-4-fold increase in antimicrobial activity against Gram-negative bacteria, but a marked decrease in both hemolytic and membrane-disrupting activities. Taken together, our findings suggest that compared with the beta-turn and alpha-helical structures, the poly-L-proline II helix is crucial for effective bacterial cell selectivity in tritrpticin and its analogs.
Yang
Sung-Tae
ST
Department of Life Science, Kwangju Institute of Science and Technology, 500-712, Kwangju, South Korea.
Yub Shin
Song Yub
SY
Kim
Yong-Chul
YC
Kim
Yangmee
Y
Hahm
Kyung-Soo
KS
Kim
Jae Il
JI
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D054804:Cathelicidins; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005658:Fungi / Q000187:drug effects; D006460:Hemolysin Proteins / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes / Q000378:metabolism; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006460:Hemolysin Proteins; D008081:Liposomes; D009842:Oligopeptides; C402895:tritrpticin; C007740:fluorexon