Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects of a synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model.
CAP18 (cationic antimicrobial protein; 18 kDa) is a neutrophil-derived protein that can bind to and inhibit various activities of lipopolysaccharide (LPS). The 37 C-terminal amino acids of CAP18 make up the LPS-binding domain. A truncated 32-amino-acid C-terminal fragment of CAP18 had potent activity against Pseudomonas aeruginosa in vitro. We studied the antimicrobial and LPS-neutralizing effects of this synthetic truncated CAP18 peptide (CAP18106-137) on lung injury in mice infected with cytotoxic P. aeruginosa. To determine its maximal effect, the CAP18106-137 peptide was mixed with bacteria just prior to tracheal instillation, and lung injury was evaluated by determining the amount of leakage of an alveolar protein tracer (125I-albumin) into the circulation and by the quantification of lung edema. The lung injury caused by the instillation of 5 x 10(5) CFU of P. aeruginosa was significantly reduced by the concomitant instillation of CAP18106-137. However, the administration of CAP18106-137 alone, without bacteria, induced lung edema, suggesting that it has some toxicity. Also, the peptide did not significantly reduce the number of bacteria that had been simultaneously instilled, nor did it significantly improve the survival of the infected mice. The addition of CAP18106-137 to aztreonam along with the bacteria did decrease the level of antibiotic-induced release of inflammatory mediators including tumor necrosis factor alpha, interleukin-6, and nitric oxide and also improved the survival of the mice. Therefore, more investigations are needed to confirm the toxicities and the therapeutic benefits of CAP18106-137 as an adjunctive therapy to antibiotics in the treatment of infections caused by gram-negative bacteria.
Sawa
T
T
Departments of Anesthesia and Medicine, The University of California, San Francisco, California 94143, USA.
Kurahashi
K
K
Ohara
M
M
Gropper
M A
MA
Doshi
V
V
Larrick
J W
JW
Wiener-Kronish
J P
JP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001398:Aztreonam / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D002352:Carrier Proteins / Q000494:pharmacology*; D054804:Cathelicidins; D004347:Drug Interactions; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011817:Rabbits
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; D054804:Cathelicidins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008997:Monobactams; D009569:Nitric Oxide; D001398:Aztreonam