Therapeutic efficacy of the magainin analogue MSI-78 in different intra-abdominal sepsis rat models.
OBJECTIVE
This study was designed to investigate the antimicrobial and anti-endotoxin activity of MSI-78, a synthetic cationic peptide analogue of magainin 2.


METHODS
The in vitro antimicrobial activity of MSI-78 was investigated against the commercially available quality control strain Escherichia coli ATCC 25922. In addition, three rat models of septic shock were investigated: (i) rats were injected intraperitoneally with 1 mg Escherichia coli 0111:B4 LPS; (ii) rats were given an intraperitoneal injection of 2 x 10(10) cfu of Escherichia coli ATCC 25922; (iii) intra-abdominal sepsis was induced via caecal ligation and puncture. All animals were randomized to receive after 360 min intravenously isotonic sodium chloride solution, 1 mg/kg MSI-78, or 60 mg/kg piperacillin. Main outcome measures were: abdominal exudate and plasma bacterial growth, plasma endotoxin and tumour necrosis factor alpha (TNF-alpha) concentrations, and lethality.


RESULTS
Our in vitro data showed that MSI-78 possesses a strong activity against Escherichia coli. The in vivo studies showed that all compounds reduced the lethality when compared to controls. MSI-78 showed a slightly higher antimicrobial activity than piperacillin and achieved a substantial decrease in endotoxin and TNF-alpha plasma concentrations than the beta-lactam.


CONCLUSIONS
Because of its strong double anti-endotoxin and antimicrobial activities MSI-78 could be an interesting compound for Gram-negative septic shock treatment.
Institute of Infectious Diseases and Public Health, Università Politecnica delle Marche, Ancona, Italy. anconacmi@interfree.it
Andrea
A
Giacometti
Roberto
R
Ghiselli
Oscar
O
Cirioni
Federico
F
Mocchegiani
Giuseppina
G
D'Amato
Fiorenza
F
Orlando
Valerio
V
Sisti
Wojciech
W
Kamysz
Carmela
C
Silvestri
Piotr
P
Naldoski
Jerzy
J
Lukasiak
Vittorio
V
Saba
Giorgio
G
Scalise
D000005:Abdomen; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000627:therapeutic use*; D002432:Cecum / Q000382:microbiology; D015169:Colony Count, Microbial; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D007274:Injections, Intraperitoneal; D008297:Male; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000627:therapeutic use; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D010878:Piperacillin / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D010406:Penicillins; D014409:Tumor Necrosis Factor-alpha; C093828:pexiganan; D010878:Piperacillin