Genetic and phenotypic identification of fusidic acid-resistant mutants with the small-colony-variant phenotype in Staphylococcus aureus.
Small-colony variants (SCVs) of Staphylococcus aureus are a slow-growing subpopulation whose phenotypes can include resistance to aminoglycosides, defects in electron transport, and enhanced persistence in mammalian cells. Here we show that a subset of mutants selected as SCVs by reduced susceptibility to aminoglycosides are resistant to the antibiotic fusidic acid (FA) and conversely that a subset of mutants selected for resistance to FA are SCVs. Mutation analysis reveals different genetic classes of FA-resistant SCVs. One class, FusA-SCVs, have amino acid substitution mutations in the ribosomal translocase EF-G different from those found in classic FusA mutants. Most of these mutations are located in structural domain V of EF-G, but some are in domain I or III. FusA-SCVs are auxotrophic for hemin. A second class of FA-resistant SCVs carry mutations in rplF, coding for ribosomal protein L6, and are designated as FusE mutants. FusE mutants fall into two phenotypic groups: one auxotrophic for hemin and the other auxotrophic for menadione. Accordingly, we have identified new genetic and phenotypic classes of FA-resistant mutants and clarified the genetic basis of a subset of S. aureus SCV mutants. A clinical implication of these data is that FA resistance could be selected by antimicrobial agents other than FA.
Norström
Tobias
T
Programme for Microbiology, Department of Cell and Molecular Biology, Box 596, Biomedical Center, Uppsala University, Uppsala, Sweden.
Lannergård
Jonas
J
Hughes
Diarmaid
D
D019943:Amino Acid Substitution; D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005672:Fusidic Acid / Q000494:pharmacology*; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009154:Mutation; D020653:Peptide Elongation Factor G / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology; D014815:Vitamins / Q000378:metabolism / Q000494:pharmacology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C492444:FusA protein, Staphylococcus aureus; D020653:Peptide Elongation Factor G; D012269:Ribosomal Proteins; D014815:Vitamins; C031249:ribosomal protein L6; D005672:Fusidic Acid; D024483:Vitamin K 3; D006427:Hemin