Methods: Community-acquired MRSA strains 1560 (a USA400 strain; AH+, TSST-1+, PVL-) and 04014 (CDC strain 368-04; AH+, TSST-1-, PVL+) were studied. MICs were determined by standard microbroth dilution. Gene expression was studied by northern blotting and/or qRT-PCR; toxins were quantitated by ELISA (PVL and TSST-1) and rabbit erythrocyte lysate assay (AH).
Results: In agreement with our previous findings, nafcillin increased production of AH, TSST-1, and PVL compared to untreated control cultures. In both MRSA strains, iclaprim and trimethoprim delayed the onset of mRNA production and shifted its peak production to later time points. Both iclaprim and trimethoprim suppressed AH production in both strains of MRSA and delayed, but did not reduce, maximal TSST-1 production in MRSA1560. Trimethoprim significantly increased maximal PVL production over both untreated and iclaprim-treated cultures.
Conclusion: The folic acid antagonist antibiotics, iclaprim and trimethoprim, altered both mRNA synthesis dynamics and protein toxin production in MRSA at concentrations below those that inhibit bacterial growth. These results, plus the fact that iclaprim is 15-fold more active than trimethoprim (MICs = 0.13 and 2.0 ug/ml, respectively), provide additional rationale for the use of iclaprim to treat complicated MRSA infections.
D. Huang, Motif Bio: Employee , Salary
D. Stevens, Motif Biosciences: Grant Investigator , Research grant
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