title: Genetic determinants of resistance to fusidic acid among clinical bacteremia isolates of Staphylococcus aureus.
abstract: Resistance to fusidic acid in Staphylococcus aureus is caused by mutation of the elongation factor G (EF-G) drug target (FusA class) or by expression of a protein that protects the drug target (FusB and FusC classes). Recently, two novel genetic classes of small-colony variants (SCVs) were identified among fusidic acid-resistant mutants selected in vitro (FusA-SCV and FusE classes). We analyzed a phylogenetically diverse collection of fusidic acid-resistant bacteremia isolates to determine which resistance classes were prevalent and whether these were associated with particular phylogenetic lineages. Each isolate was shown by DNA sequencing and plasmid curing to carry only one determinant of fusidic acid resistance, with approximately equal frequencies of the FusA, FusB, and FusC genetic classes. The FusA class (mutations in fusA) were distributed among different phylogenetic types. Two distinct variants of the FusC class (chromosomal fusC gene) were identified, and FusC was also distributed among different phylogenetic types. In contrast, the FusB class (carrying fusB on a plasmid) was found in closely related types. No FusE-class mutants (carrying mutations in rplF) were found. However, one FusA-class isolate had multiple mutations in the fusA gene, including one altering a codon associated with the FusA-SCV class. SCVs are frequently unstable and may undergo compensatory evolution to a normal growth phenotype after their initial occurrence. Accordingly, this normal-growth isolate might have evolved from a fusidic acid-resistant SCV. We conclude that at least three different resistance classes are prevalent among fusidic acid-resistant bacteremia isolates of S. aureus.
authors.affiliation: Microbiology Programme, Department of Cell and Molecular Biology, Box 596, Biomedical Center, Uppsala University, S-75124 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Lannergård
authors.forename: Tobias
authors.initials: T
authors.lastname: Norström
authors.forename: Diarmaid
authors.initials: D
authors.lastname: Hughes
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000382:microbiology*; D001426:Bacterial Proteins / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005672:Fusidic Acid / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020653:Peptide Elongation Factor G / Q000235:genetics; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C492444:FusA protein, Staphylococcus aureus; C492443:FusB protein, Staphylococcus aureus; D020653:Peptide Elongation Factor G; D005672:Fusidic Acid