Antibiotic activity and structural analysis of the scorpion-derived antimicrobial peptide IsCT and its analogs.
IsCT is a non-cell-selective antimicrobial peptide isolated from the scorpion Opisthacanthus madagascariensis that has potent cytolytic activity against both mammalian and bacterial cells. To investigate the structure-activity relationships of IsCT and to design novel peptide antibiotics with bacterial cell selectivity, we synthesized several analogs of IsCT and determined their three-dimensional structures in solution by 2D-NMR spectroscopy. IsCT has a linear alpha-helical structure from Gly3 to Phe13, and [K7]-IsCT has a linear alpha-helical structure from Leu2 to Phe13. [K7, P8, K11]-IsCT, which has a bend in its middle region, exhibited the highest antibacterial activity without hemolytic activity, suggesting that its proline-induced bend is an important determinant of this selectivity. Tryptophan fluorescence showed that the high selectivity of [K7, P8, K11]-IsCT toward bacterial cells is closely correlated with its highly selective interaction with negatively charged phospholipids. Its potent activity against antibiotic-resistant bacteria suggests that [K7, P8, K11]-IsCT may serve as a promising lead candidate in the development of new peptide antibiotics.
Lee
Kyungik
K
Department of Chemistry and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea.
Shin
Song Yub
SY
Kim
Kyoungho
K
Lim
Shin Saeng
SS
Hahm
Kyung-Soo
KS
Kim
Yangmee
Y
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012604:Scorpion Venoms / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; C435485:IsCT protein, Opisthacanthus madagascariensis; D012604:Scorpion Venoms