title: Oxacillin alters the toxin expression profile of community-associated methicillin-resistant Staphylococcus aureus.
abstract: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing cause for concern. These strains are more virulent than health care-associated MRSA (HA-MRSA) due to higher levels of toxin expression. In a previous study, we showed that the high-level expression of PBP2a, the alternative penicillin binding protein encoded by the mecA gene on type II staphylococcal cassette chromosome mec (SCCmec) elements, reduced toxicity by interfering with the Agr quorum sensing system. This was not seen in strains carrying the CA-MRSA-associated type IV SCCmec element. These strains express significantly lower levels of PBP2a than the other MRSA type, which may explain their relatively high toxicity. We hypothesized that as oxacillin is known to increase mecA expression levels, it may be possible to attenuate the toxicity of CA-MRSA by using this antibiotic. Subinhibitory oxacillin concentrations induced PBP2a expression, repressed Agr activity, and, as a consequence, decreased phenol-soluble modulin (PSM) secretion by CA-MRSA strains. However, consistent with other studies, oxacillin also increased the expression levels of alpha-toxin and Panton-Valentine leucocidin (PVL). The net effect of these changes on the ability to lyse diverse cell types was tested, and we found that where the PSMs and alpha-toxin are important, oxacillin reduced overall lytic activity, but where PVL is important, it increased lytic activity, demonstrating the pleiotropic effect of oxacillin on toxin expression by CA-MRSA.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.
authors.forename: Justine K
authors.initials: JK
authors.lastname: Rudkin
authors.forename: Maisem
authors.initials: M
authors.lastname: Laabei
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Hwang-Soo
authors.initials: HS
authors.lastname: Joo
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Lennon
authors.forename: James P
authors.initials: JP
authors.lastname: O'Gara
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Waterfield
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Massey
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D017714:Community-Acquired Infections / Q000382:microbiology; D005098:Exotoxins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006460:Hemolysin Proteins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007956:Leukocidins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D010068:Oxacillin / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects; D013203:Staphylococcal Infections / Q000382:microbiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D006460:Hemolysin Proteins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D046915:Penicillin-Binding Proteins; D015534:Trans-Activators; C487789:mecA protein, Staphylococcus aureus; C021091:staphylococcal alpha-toxin; C025971:staphylococcal delta toxin; D010068:Oxacillin