title: Beta-lactams interfering with PBP1 induce Panton-Valentine leukocidin expression by triggering sarA and rot global regulators of Staphylococcus aureus.
abstract: Previous articles reported that beta-lactam antibiotics increase the expression of Staphylococcus aureus Panton-Valentine leukocidin (PVL) by activating its transcription. We investigated the mechanisms underlying the inductor effect of beta-lactams on PVL expression by determining targets and regulatory pathways possibly implicated in this process. We measured PVL production in the presence of oxacillin (nonselective), imipenem (penicillin-binding protein 1 [PBP1] selective), cefotaxime (PBP2 selective), cefaclore (PBP3 selective), and cefoxitin (PBP4 selective). In vitro, we observed increased PVL production consistent with luk-PV mRNA levels that were 20 to 25 times higher for community-acquired methicillin-resistant S. aureus (CA-MRSA) cultures treated with PBP1-binding oxacillin and imipenem than for cultures treated with other beta-lactams or no antibiotic at all. This effect was also observed in vivo, with increased PVL mRNA levels in lung tissues from CA-MRSA-infected mice treated with imipenem but not cefoxitin. To confirm the involvement of PBP1 inhibition in this pathway, PBP1 depletion by use of an inducible pbp1 antisense RNA showed a dose-dependent relationship between the level of pbp1 antisense RNA and the luk-PV mRNA level. Upon imipenem treatment of exponential-phase cultures, we observed an increased sarA mRNA level after 30 min of incubation followed by a decreased rot mRNA level after 1 to 4 h of incubation. Unlike the agr and saeRS positive regulators, which were nonessential for PVL induction by beta-lactams, the sarA (positive) and rot (negative) PVL regulators were necessary for PVL induction by imipenem. Our results suggest that antibiotics binding to PBP1 increase PVL expression by modulating sarA and rot, which are essential mediators of the inductor effect of beta-lactams on PVL expression.
authors.affiliation: Faculté Lyon Est, INSERM, U851, and Université de Lyon, Centre National de Référence des Staphylocoques, Lyon F-69008, France. oana.dumitrescu@chu-lyon.fr
authors.forename: Oana
authors.initials: O
authors.lastname: Dumitrescu
authors.forename: Priya
authors.initials: P
authors.lastname: Choudhury
authors.forename: Sandrine
authors.initials: S
authors.lastname: Boisset
authors.forename: Cédric
authors.initials: C
authors.lastname: Badiou
authors.forename: Michele
authors.initials: M
authors.lastname: Bes
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Benito
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolz
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.forename: Jerome
authors.initials: J
authors.lastname: Etienne
authors.forename: Ambrose L
authors.initials: AL
authors.lastname: Cheung
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Bowden
authors.forename: Gerard
authors.initials: G
authors.lastname: Lina
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics*; D001427:Bacterial Toxins / Q000235:genetics*; D002433:Cefaclor / Q000494:pharmacology; D002439:Cefotaxime / Q000494:pharmacology; D002440:Cefoxitin / Q000494:pharmacology; D005098:Exotoxins / Q000235:genetics*; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D015378:Imipenem / Q000494:pharmacology; D007956:Leukocidins / Q000235:genetics*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D046915:Penicillin-Binding Proteins; D012097:Repressor Proteins; C088021:SarA protein, bacterial; D015534:Trans-Activators; D047090:beta-Lactams; C408643:rot protein, Staphylococcus aureus; D002433:Cefaclor; D002440:Cefoxitin; D015378:Imipenem; D002439:Cefotaxime; D010068:Oxacillin