Subinhibitory fluoroquinolone exposure selects for reduced beta-lactam susceptibility in methicillin-resistant Staphylococcus aureus and alterations in the SOS-mediated response.
Growth of fluoroquinolone (FQ)-susceptible methicillin-resistant Staphylococcus aureus (MRSA) in the presence of sub-MIC FQ has been shown to enhance methicillin resistance in traditional nosocomial MRSA isolates. We aimed to confirm this phenomenon in nine community-associated MRSA (CA-MRSA) clinical isolates, and to identify candidate genes that might account for this unusual phenotype. Overnight growth of CA-MRSA strains in tryptic soy broth containing a subinhibitory concentration of either ciprofloxacin or levofloxacin resulted in a concentration-related increase in the number of colonies that grew on nafcillin agar, such that about one CFU in four exhibited significantly higher resistance to nafcillin, with only a modest increase in FQ MIC. No mutations were found in the quinolone-resistance determining region of gyrA and grlA. DNA microarray studies of a representative levofloxacin-exposed clone found that gene expression was increased for 53 open reading frames (ORFs), including norR and mecA, and decreased for 10. The majority of these ORFs encode regulatory and stress response proteins. In conclusion, sublethal exposure to FQ alters the SOS response in CA-MRSA and selects in a non-lethal manner for stable mutants with enhanced expression of methicillin resistance.
Division of Infectious Diseases, San Francisco General Hospital, University of California, San Francisco, CA 94110, USA. pierre.tattevin@chu-rennes.fr
Pierre
P
Tattevin
Li
L
Basuino
Henry F
HF
Chambers
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D002939:Ciprofloxacin / Q000494:pharmacology; D017714:Community-Acquired Infections / Q000382:microbiology; D027081:DNA Gyrase / Q000235:genetics; D004252:DNA Mutational Analysis; D004251:DNA Transposable Elements; D024841:Fluoroquinolones / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D064704:Levofloxacin; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D009254:Nafcillin / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins; D013014:SOS Response, Genetics / Q000187:drug effects*; D012641:Selection, Genetic; D013203:Staphylococcal Infections / Q000382:microbiology; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D018440:beta-Lactam Resistance; D047090:beta-Lactams / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004251:DNA Transposable Elements; D024841:Fluoroquinolones; C474646:NorR protein, Staphylococcus aureus; D046915:Penicillin-Binding Proteins; D014157:Transcription Factors; D047090:beta-Lactams; C487789:mecA protein, Staphylococcus aureus; D009254:Nafcillin; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D027081:DNA Gyrase