Chemotherapeutic activity of synthetic antimicrobial peptides: correlation between chemotherapeutic activity and neutrophil‐activating activity

Abstract

The chemotherapeutic activity of three synthetic antibacterial peptides was investigated. KLKLLLLLKLK-NH 2 and its D-enantiomer showed significant chemotherapeutic activity in MRSA-infected mice, whereas KLKLLLKLK-NH 2 , which showed the highest antibacterial activity among them in vitro, was found to have almost no ability to prevent MRSA infection. These results suggest that the antibacterial activity of peptides assessed in vitro does not necessarily correlate with their chemotherapeutic activity. We found that KLKLLLLLKLK-NH 2 and its D-enantiomer, but not KLKLLLKLK-NH 2 , have the ability to activate human neutrophils to produce Superoxide, suggesting that the prevention of MRSA infection by these peptides is not simply due to their direct bactericidal activity but to augmentation of the systemic defense mechanism mediated by neutrophils.

Prevention of Death in Bacterium-Infected Mice by a Synthetic Antimicrobial Peptide, L5, through Activation of Host Immunity

“…On the other hand, KLKLLLKLK-NH 2 (L3) was found to exhibit strong antibacterial activity in vitro but not the ability to prevent MRSA infection. We also found that L5 and DL5, but not L3, activate human neutrophils (15). Furthermore, we previously reported that L5 binds to calreticulin on the cell surface of human neutrophils and retinoic acid-treated U937 (a human monocyte cell line) (4,5).…”

“…Working with the structure of this peptide, we further optimized the sequences and finally obtained a cationic antimicrobial peptide-KLKLLLLLKLK-NH 2 (L5) (1). L5 and its d-enantiomer (DL5) were found to show significant efficacy in prophylactic treatment of methicillin-resistant Staphylococcus aureus (MRSA)-infected mice (15). On the other hand, KLKLLLKLK-NH 2 (L3) was found to exhibit strong antibacterial activity in vitro but not the ability to prevent MRSA infection.…”

Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation.

“…In addition, this hypothesis is supported by reports on the in vitro chemotactic activity of neutrophil defensins for lymphocytes and monocytes (5,6), and the capacity of high concentrations (100 g/ml) to induce IL-8 secretion from epithelial cells (7). Activation of accumulated neutrophils by HNP-1 is another possible explanation, but in vitro studies demonstrate that neutrophil defensins decrease phagocytosis and the associated production of reactive oxygen intermediates (24). We cannot exclude the possibility that the opsonic activity of neutrophil defensins (25) contributes to the observed in vivo antibacterial activity.…”

Activity and Mechanism of Antimicrobial Peptide-Mimetic Amphiphilic Polymethacrylate Derivatives

“…These properties support new peptidomimetic designs that incorporate the physiochemical parameters found in antimicrobial peptides such as their cationic charge, hydrophobicity, and amphiphilic structures which are key determinants in the mode of antimicrobial action [3][4][5][6]. This design approach has been successfully generalized to abiotic oligomers and macromolecules such as designed synthetic peptides [7][8][9] and peptidomimetics including β-peptides [10][11][12], arylamides [13], and peptoids [14,15]. These peptides and their mimics are a good basis for new antibiotics, however, issues associated with low stability in vivo, unknown systemic toxicity, and high manufacturing cost present challenges to their implementation as therapeutic agents or in biomedicine.…”