β-Lactams Interfering with PBP1 Induce Panton-Valentine Leukocidin Expression by Triggering sarA and rot Global Regulators of Staphylococcus aureus
- 1 July 2011
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 55 (7), 3261-3271
- https://doi.org/10.1128/aac.01401-10
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.Keywords
This publication has 64 references indexed in Scilit:
- Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injuryProceedings of the National Academy of Sciences of the United States of America, 2010
- Presence of Genes Encoding the Panton-Valentine Leukocidin Exotoxin Is Not the Primary Determinant of Outcome in Patients with Complicated Skin and Skin Structure Infections Due to Methicillin-Resistant Staphylococcus aureus: Results of a Multinational TrialJournal of Clinical Microbiology, 2009
- Evidence for a dual role of PBP1 in the cell division and cell separation of Staphylococcus aureusMolecular Microbiology, 2009
- The Panton–Valentine leukocidin vaccine protects mice against lung and skin infections caused by Staphylococcus aureus USA300Clinical Microbiology & Infection, 2009
- Contribution of Panton-Valentine Leukocidin in Community-Associated Methicillin-Resistant Staphylococcus aureus PathogenesisPLOS ONE, 2008
- The Virulence Regulator Sae ofStaphylococcus aureus:Promoter Activities and Response to Phagocytosis-Related SignalsJournal of Bacteriology, 2008
- Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanismGenes & Development, 2007
- Role of PBP1 in Cell Division of Staphylococcus aureusJournal of Bacteriology, 2007
- Effect of Antibiotics on Staphylococcus aureus Producing Panton-Valentine LeukocidinAntimicrobial Agents and Chemotherapy, 2007
- The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophageNature, 1983