title: Accessory gene regulator (agr) locus in geographically diverse Staphylococcus aureus isolates with reduced susceptibility to vancomycin.
abstract: The majority of infections with glycopeptide intermediate-level resistant Staphylococcus aureus (GISA) originate in biomedical devices, suggesting a possible increased ability of these strains to produce biofilm. Loss of function of the accessory gene regulator (agr) of S. aureus has been suggested to confer an enhanced ability to bind to polystyrene. We studied agr in GISA, hetero-GISA, and related glycopeptide-susceptible S. aureus isolates. All GISA strains from diverse geographic origins belong to agr group II. All GISA strains were defective in agr function, as demonstrated by their inability to produce delta-hemolysin. Hetero-GISA isolate A5940 demonstrated a nonsense mutation in agrA that was not present in a pulsed-field gel electrophoresis-indistinguishable vancomycin-susceptible isolate from the same patient. Various other agr point mutations were noted in several clinical GISA and hetero-GISA isolates. A laboratory-generated agr-null strain demonstrated a small but reproducible increase in vancomycin heteroresistance after growth in vitro in subinhibitory concentrations of vancomycin. This was not seen in the isogenic agr group II parent strain in which agr was intact. The in vitro bactericidal activity of vancomycin was attenuated in the agr-null strain compared to the parent strain. These findings imply that compromised agr function is advantageous to clinical isolates of S. aureus toward the development of vancomycin heteroresistance, perhaps through the development of vancomycin tolerance.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. gsakoulas@caregroup.harvard.edu
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: George M
authors.initials: GM
authors.lastname: Eliopoulos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Moellering
authors.forename: Christine
authors.initials: C
authors.lastname: Wennersten
authors.forename: Lata
authors.initials: L
authors.lastname: Venkataraman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Novick
authors.forename: Howard S
authors.initials: HS
authors.lastname: Gold
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D006460:Hemolysin Proteins; D006461:Hemolysis; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D012150:Polymorphism, Restriction Fragment Length; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000453:epidemiology / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification*; D015534:Trans-Activators / Q000235:genetics*; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000235:genetics*
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006460:Hemolysin Proteins; D015534:Trans-Activators; D014640:Vancomycin; C025994:delta hemolysin protein, Staphylococcus aureus