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Antimicrobial Agents and Chemotherapy, April 2005, p. 1377-1380, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1377-1380.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Azithromycin Exhibits Bactericidal Effects on Pseudomonas aeruginosa through Interaction with the Outer Membrane

Yoshifumi Imamura,1 Yasuhito Higashiyama,1* Kazunori Tomono,1 Koichi Izumikawa,1 Katsunori Yanagihara,1 Hideaki Ohno,1 Yoshitsugu Miyazaki,1 Yoichi Hirakata,1 Yohei Mizuta,1 Jun-ichi Kadota,1 Barbara H. Iglewski,2 and Shigeru Kohno1

Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan,1 Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York2

Received 10 August 2004/ Returned for modification 28 November 2004/ Accepted 21 December 2004

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.

* Corresponding author. Mailing address: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. Phone: 81-95-849-7273. Fax: 81-95-849-7285. E-mail: higashi-ngs{at}umin.ac.jp.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1377-1380, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1377-1380.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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