Beta-lactam antibiotics potentiate magainin 2 antimicrobial activity in vitro and in vivo.
The ability of magainin 2 to augment antibiotic therapy was examined. Susceptibility to magainin 2 was determined on Escherichia coli incubated in the presence and absence of sublethal concentrations of antibiotics both in vitro and in vivo. Experiments in buffer and normal human serum revealed that E. coli exposed to sublethal amounts of cefepime, a beta-lactam antibiotic, was significantly more susceptible to the antimicrobial activity of magainin 2. Bacteria incubated with subinhibitory concentrations of other beta-lactam type antibiotics, but not amikacin (an aminoglycoside) or ciprofloxacin (a quinolone), were also more susceptible to magainin 2 in normal human serum. Bacteria were less susceptible to magainin 2 when they were examined in heat-inactivated serum. Complement was shown to be required for magainin 2 activity in serum by using C8-deficient sera. The combination of magainin 2 and cefepime was shown to be more antimicrobial in normal human serum for a variety of bacterial strains. Magainin 2 was completely inactive as a therapeutic agent when it was administered alone (2 mg per mouse) but significantly increased the survival of mice when it was administered with a low level of cefepime.
Anti-Infective Therapy, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
R P
RP
Darveau
M D
MD
Cunningham
C L
CL
Seachord
L
L
Cassiano-Clough
W L
WL
Cosand
J
J
Blake
C S
CS
Watkins
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects; D054806:Magainins; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D029867:Xenopus Proteins
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D002511:Cephalosporins; D054806:Magainins; D010455:Peptides; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus; D000077723:Cefepime