N-Acylated and d Enantiomer Derivatives of a Nonamer Core Peptide of Lactoferricin B Showing Improved Antimicrobial Activity

Abstract

N-acylated or d enantiomer peptide derivatives based on the sequence RRWQWRMKK in lactoferricin B demonstrated antimicrobial activities greater than those of lactoferricin B against bacteria and fungi. The most potent peptide, conjugated with an 11-carbon-chain acyl group, showed two to eight times lower MIC than lactoferricin B.

Comparative antimicrobial activity and mechanism of action of bovine lactoferricin-derived synthetic peptides

“…By adopting this structure, LfcinB becomes markedly amphipathic with clear hydrophobic and positively charged faces, which is a trait they share with other peptides that display antimicrobial activity. Previous studies demonstrated that shorter LfcinBrelated peptides with N-acylated or D enantiomer properties showed antimicrobial activities greater than LfcinB against bacteria and fungi (Wakabayashi et al 1999). In our study, Lfcin9 did not show any antimicrobial activities and Lfcin11 had four to eight times higher MIC than LfcinB, which may be related to the absence of N-acylation.…”

Chain length dependence of antimicrobial peptide–fatty acid conjugate activity

“…Our previous work [17], along with the work of several other groups [16,18,19,21,29], demonstrates that conjugation of antimicrobial peptides with fatty acids can enhance their membrane lytic activity. We believe the increase in activity is due to the increased hydrophobic attraction to membranes caused by the addition of the fatty acid tail.…”

“…1) can modify both the activity and selectivity of the peptide [15][16][17][18][19][20][21]. In earlier work from our lab we determined that conjugation of a peptide to a fatty acid can increase the antimicrobial activity of amphipathic peptides [17,20].…”

Lactoferricin

“…LfcinB is bactericidal and LfcinH, like bLF and hLF, is bacteriostatic against a wide variety of Gram-negative and Gram-positive bacteria (table 1) [8][9][10][11][12]. This lack of species specifi city combined with the observation that both the L and D enantiomers of LfcinB are active suggests that the bacterial target of this peptide is a structure of a generalized nature, a prime candidate being the phospholipids present in membranes [13]. As both the lipopolysaccharide (LPS)-containing outer membrane of Gram-negative bacteria and the teichoic acid layer that surrounds the cytoplasmic membrane of Gram-positive bacteria are negatively charged surfaces, it is thought that an electrostatic attraction fi rst binds the cationic peptide to the outside of the bacterial cell.…”

“…The QSAR and multivariable analysis techniques are also membrane. The importance of the initial electrostatic interaction is highlighted fi rst by the high overall positive charge of the peptides, with a net charge of at least +4 necessary for optimal antibacterial activity [28]; second by the fact that murine Lfcin (LfcinM), which contains two Glu residues, lacks antibacterial activity (table 2) [29]; and third by the increased activity of C-terminally amidated unadecapeptides derived from various Lfcins [13,28]. As Arg can interact both electrostatically and through multiple hydrogen bonds with the negatively charged surface of the bacteria, it is thought that this amino acid is the most effective for targeting the peptide to the membrane.…”