Development of homogeneous expression of resistance in methicillin-resistant Staphylococcus aureus clinical strains is functionally associated with a β-lactam-mediated SOS response
Open Access
- 20 May 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Antimicrobial Chemotherapy
- Vol. 64 (1), 37-45
- https://doi.org/10.1093/jac/dkp164
Abstract
One of the main characteristics of methicillin-resistant Staphylococcus aureus (MRSA) from both hospitals and community is their heterogeneous expression of resistance. Recently, we reported new heterogeneous MRSA isolates phenotypically susceptible to oxacillin despite being mecA positive. These low-level mecA-mediated resistance MRSA strains are very heterogeneous in expression (HeR) and are likely to be clinically relevant since exposure of such isolates to β-lactams can result in high-level homotypic resistance (HoR). We hypothesized that HeR to HoR selection in these clinically relevant strains may be determined by the pre-existence of a hypermutable population that favours its selection in the presence of oxacillin. Using established procedures, SA13011 HeR to HoR selection was performed by using subinhibitory concentrations of oxacillin and examined for mutability. Real-time RT-PCR and transcriptional profiling by DNA microarray were used to compare gene expression between both populations and related genetically modified SA13011 strain. We found that HeR/HoR selection by oxacillin was associated with increased mutation rate and oxacillin-mediated SOS response. We determined increased expression of both mecA and SOS response lexA/recA regulators. Mutational inactivation of lexA repressor resulted in a significant decrease in both mutation rate and oxacillin resistance in the HoR cells. Complementation of the lexA mutant strain restored oxacillin resistance to the high levels observed in the corresponding HoR wild-type strain. The present results support the notion that SOS response is mechanistically involved in generating mutations that, in addition to mecA induction, allow the selection of a highly oxacillin-resistant population.Keywords
This publication has 33 references indexed in Scilit:
- Increased mutability of Pseudomonas aeruginosa in biofilmsJournal of Antimicrobial Chemotherapy, 2008
- Identification and Phenotypic Characterization of a β-Lactam-Dependent, Methicillin-Resistant Staphylococcus aureus StrainAntimicrobial Agents and Chemotherapy, 2007
- Detection of low-level oxacillin resistance in mecA-positive Staphylococcus aureusClinical Microbiology & Infection, 2007
- β-Lactam Antibiotics Induce the SOS Response and Horizontal Transfer of Virulence Factors inStaphylococcus aureusJournal of Bacteriology, 2006
- Induction of the SOS regulon of Haemophilus influenzae does not affect phase variation rates at tetranucleotide or dinucleotide repeatsMicrobiology, 2005
- Inhibition of Mutation and Combating the Evolution of Antibiotic ResistancePLoS Biology, 2005
- SOS-Independent Induction ofdinBTranscription by β-Lactam-Mediated Inhibition of Cell Wall Synthesis inEscherichia coliJournal of Bacteriology, 2005
- DpiA Binding to the Replication Origin ofEscherichia coliPlasmids and Chromosomes Destabilizes Plasmid Inheritance and Induces the Bacterial SOS ResponseJournal of Bacteriology, 2003
- Conversion of Oxacillin-Resistant Staphylococci from Heterotypic to Homotypic Resistance ExpressionAntimicrobial Agents and Chemotherapy, 2002
- Penicillin‐binding proteins of β‐lactam‐resistant strains of Staphylococcus aureusFEBS Letters, 1985