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AMB Express
2012 Dec 13;21:67. doi: 10.1186/2191-0855-2-67.
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Anti-infectious and anti-inflammatory effects of peptide fragments sequentially derived from the antimicrobial peptide centrocin 1 isolated from the green sea urchin, Strongylocentrotus droebachiensis.
Björn C
,
Håkansson J
,
Myhrman E
,
Sjöstrand V
,
Haug T
,
Lindgren K
,
Blencke HM
,
Stensvåg K
,
Mahlapuu M
.
Abstract
Bacterial resistance against antibiotic treatment has become a major threat to public health. Antimicrobial peptides (AMPs) have emerged as promising alternative agents for treatment of infectious diseases. This study characterizes novel synthetic peptides sequentially derived from the AMP centrocin 1, isolated from the green sea urchin, for their applicability as anti-infective agents.The microbicidal effect of centrocin 1 heavy chain (CEN1 HC-Br), its debrominated analogue (CEN1 HC), the C-terminal truncated variants of both peptides, i.e. CEN1 HC-Br (1-20) and CEN1 HC (1-20), as well as the cysteine to serine substituted equivalent CEN1 HC (Ser) was evaluated using minimal microbicidal concentration assay. The anti-inflammatory properties were assessed by measuring the inhibition of secretion of pro-inflammatory cytokines. All the peptides tested exhibited marked microbicidal and anti-inflammatory properties. No difference in efficacy was seen comparing CEN1 HC-Br and CEN1 HC, while the brominated variant had higher cytotoxicity. C-terminal truncation of both peptides reduced salt-tolerability of the microbicidal effect as well as anti-inflammatory actions. Also, serine substitution of cysteine residue decreased the microbicidal effect. Thus, from the peptide variants tested, CEN1 HC showed the best efficacy and safety profile. Further, CEN1 HC significantly reduced bacterial counts in two different animal models of infected wounds, while Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance against this peptide under continued selection pressure. In summary, CEN1 HC appears a promising new antimicrobial agent, and clinical studies are warranted to evaluate the applicability of this AMP for local treatment of infections in man.
Figure 1. Effects of CEN1 HC-Br (a), CEN1 HC (b), CEN1 HC (1–20) (c) and CEN1 HC (Ser) (d) on TNF-α secretion from THP-1 cells. The peptides were added to PMA treated THP-1 cells in triplicate 30 min after the addition of LPS (0.1 ng/mL). Peptide concentrations ranging from 0.04 to 50 mg/L of CEN1 HC and CEN1 HC-Br, 0.04 to 500 mg/L of CEN1 HC (Ser) and 1 to 500 mg/L of CEN1 HC (1–20) were tested. Cytokine levels were measured in the cell supernatants by ELISA after six hours of stimulation. Data are presented as mean ± SEM with stimulated cytokine levels without peptide added set to 0%. Data was fitted to curves using a 4-parameter fit in the Origin software. The IC50 values were automatically calculated by the software. Due to an unsatisfactory curve fitting, IC50 for CEN1 HC-Br was estimated to be approximately 4 mg/L.
Figure 2. Effects of CEN1 HC-Br (a), CEN1 HC (b) and CEN1 HC (1–20) (c) on IL-6 secretion from THP-1 cells. The peptides were added to PMA treated THP-1 cells in triplicate 30 min after the addition of LPS (0.1 ng/mL). Peptide concentrations ranging from 0.04 to 50 mg/L of CEN1 HC and CEN1 HC-Br, and 1 to 500 mg/L CEN1 HC (1–20) were tested. Cytokine levels were measured in the cell supernatants by ELISA after six hours of stimulation. Data are presented as mean ± SEM with stimulated cytokine levels without peptide added set to 0%. Data was fitted to curves using a 4-parameter fit in the Origin software. The IC50 values were automatically calculated by the software.
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