Document Detail

Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria.
MedLine Citation:
PMID:  8383945     Owner:  NLM     Status:  MEDLINE    
Mutations which severely affect the function of the outer membrane of Escherichia coli and Salmonella typhimurium (lpxA and firA mutations of lipid A synthesis and rfaE mutation of the lipopolysaccharide inner-core synthesis) were found to decrease the MICs of erythromycin, roxithromycin, clarithromycin, and azithromycin by factors of 32 to 512, 32 to 1,024, 64 to 512, and 16 to 64, respectively. The sensitization factors for three other hydrophobic antibiotics (rifampin, fusidic acid, and mupirocin) ranged from 16 to 300. The outer membrane permeability-increasing agents polymyxin B nonapeptide (3 micrograms/ml) and deacylpolymyxin B (1 microgram/ml) sensitized wild-type E. coli to azithromycin by factors of 10 and 30, respectively. Quantitatively very similar sensitization to the other macrolides took place. Polymyxin-resistant pmrA mutants of S. typhimurium displayed no cross-resistance to azithromycin. Proteus mirabilis mutants which were sensitized to polymyxin by a factor of > or = 300 to > or = 1,000 had a maximal two- to fourfold increase in sensitivity to azithromycin. These results indicate that azithromycin and the other new macrolides use the hydrophobic pathway across the outer membrane and that the intact outer membrane is an effective barrier against them. Furthermore, the results indicate that azithromycin, in contrast to polymyxin, does not effectively diffuse through the outer membrane by interacting electrostatically with the lipopolysaccharide.
M Vaara
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  37     ISSN:  0066-4804     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  1993 Feb 
Date Detail:
Created Date:  1993-04-15     Completed Date:  1993-04-15     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  354-6     Citation Subset:  IM    
Department of Bacteriology and Immunology, University of Helsinki, Finland.
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MeSH Terms
Cell Membrane / drug effects,  metabolism
Clarithromycin / pharmacology*
Erythromycin / analogs & derivatives*,  pharmacology
Escherichia coli / drug effects,  genetics
Gram-Negative Bacteria / drug effects*,  genetics
Lipopolysaccharides / metabolism
Microbial Sensitivity Tests
Polymyxins / pharmacology
Roxithromycin / pharmacology*
Salmonella typhimurium / drug effects,  genetics
Reg. No./Substance:
0/Lipopolysaccharides; 0/Polymyxins; 114-07-8/Erythromycin; 80214-83-1/Roxithromycin; 81103-11-9/Clarithromycin; 83905-01-5/Azithromycin

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