Affiliation:
1. Department of Bacteriology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima City, Hiroshima
2. Institute for Medical Microbiology, University of Zürich, Zürich, Switzerland
Abstract
ABSTRACT
An association between moenomycin resistance and vancomycin intermediate resistance in
Staphylococcus aureus
was demonstrated previously. Thus, to elucidate the mechanism of vancomycin intermediate resistance, we searched for factors contributing to moenomycin resistance. Random Tn
551
insertional mutagenesis of methicillin-resistant
S. aureus
strain COL yielded three mutants with decreased susceptibilities to moenomycin. Correspondingly, these mutants also exhibited slightly decreased susceptibilities to vancomycin. Genetic analysis revealed that two of the mutants had Tn
551
insertions in the
fmtC
(
mprF
) gene, which is associated with the synthesis of lysyl-phosphatidylglycerol. The third Tn
551
insertion was located in the
lysC
gene, which is involved in the biosynthesis of lysine from aspartic acid. Consequently, mutations in both of these loci reduced the lysyl-phosphatidylglycerol content in the cell membrane, giving it a more negative net charge. The positively charged antibiotic gentamicin and cationic antimicrobial peptides such as β-defensins and CAP18 were more effective against the mutants. The levels of moenomycin and vancomycin binding to intact cells was also greater in the mutants than in the wild type, while the binding affinity was not altered when cells boiled in sodium dodecyl sulfate were used, indicating that both agents had higher affinities for the negatively charged membranes of the mutants. Therefore, the membrane charge of
S. aureus
appears to influence the efficacies of moenomycin, vancomycin, and other cationic antimicrobial agents.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
123 articles.
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