Azithromycin exhibits bactericidal effects on Pseudomonas aeruginosa through interaction with the outer membrane.
The aim of the present study was to elucidate the effect of the macrolide antibiotic azithromycin on Pseudomonas aeruginosa. We studied the susceptibility to azithromycin in P. aeruginosa PAO1 using a killing assay. PAO1 cells at the exponential growth phase were resistant to azithromycin. In contrast, PAO1 cells at the stationary growth phase were sensitive to azithromycin. The divalent cations Mg2+ and Ca2+ inhibited this activity, suggesting that the action of azithromycin is mediated by interaction with the outer membranes of the cells, since the divalent cations exist between adjacent lipopolysaccharides (LPSs) and stabilize the outer membrane. The divalent cation chelator EDTA behaved in a manner resembling that of azithromycin; EDTA killed more PAO1 in the stationary growth phase than in the exponential growth phase. A 1-N-phenylnaphthylamine assay showed that azithromycin interacted with the outer membrane of P. aeruginosa PAO1 and increased its permeability while Mg2+ and Ca2+ antagonized this action. Our results indicate that azithromycin directly interacts with the outer membrane of P. aeruginosa PAO1 by displacement of divalent cations from their binding sites on LPS. This action explains, at least in part, the effectiveness of sub-MICs of macrolide antibiotics in pseudomonal chronic airway infection.
Imamura
Yoshifumi
Y
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Higashiyama
Yasuhito
Y
Tomono
Kazunori
K
Izumikawa
Koichi
K
Yanagihara
Katsunori
K
Ohno
Hideaki
H
Miyazaki
Yoshitsugu
Y
Hirakata
Yoichi
Y
Mizuta
Yohei
Y
Kadota
Jun-Ichi
J
Iglewski
Barbara H
BH
Kohno
Shigeru
S
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development*
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D017963:Azithromycin