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      Effects of Iclaprim and Trimethoprim on Exotoxin Production by Methicillin-resistant Staphylococcus aureus

      abstract
      , PhD 1 , , BA 1 , , MD, PhD 2 , , MD, PhD 1
      Open Forum Infectious Diseases
      Oxford University Press

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          Abstract

          Background

          Methicillin-resistant Staphylococcus aureus (MRSA) causes serious, often life-threatening, infections. Exotoxins such as alpha-hemolysin (AH), Panton Valentine leukocidin (PVL), and Toxic shock syndrome toxin 1 (TSST-1) mediate pathogenesis and inhibition of toxin production is an important consideration in choosing appropriate treatments. Vancomycin is recommended for severe MRSA infections; however, increasing vancomycin resistance, poor clinical outcomes and nephrotoxicity are serious concerns. Thus newer agents are needed, including those that block bacterial toxin production. In the current study, we compared the effects of sub-inhibitory doses (sub-MIC) of two folic acid inhibitor antibiotics (iclaprim, trimethoprim) with cell wall-active agents (nafcillin, vancomycin) on transcription and translation of AH, PVL and TSST-1 in two clinical MRSA isolates.

          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 with 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.

          Disclosures

          A. Bryant, Motif Biosciences: Grant Investigator, Research grant; D. Huang, Motif Bio: Employee, Salary; D. Stevens, Motif Biosciences: Grant Investigator, Research grant

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          Author and article information

          Journal
          Open Forum Infect Dis
          Open Forum Infect Dis
          ofid
          Open Forum Infectious Diseases
          Oxford University Press (US )
          2328-8957
          Fall 2017
          04 October 2017
          04 October 2017
          : 4
          : Suppl 1 , ID Week 2017 Abstracts
          : S372-S373
          Affiliations
          [1 ] Infectious Diseases, Veterans Affairs Medical Center , Boise, Idaho
          [2 ] Motif BioSciences , New York, New York
          Author notes

          Session: 147. Expanded Spectrum – New Antimicrobial Susceptibility Testing

          Friday, October 6, 2017: 12:30 PM

          Article
          ofx163.915
          10.1093/ofid/ofx163.915
          5630768
          071aec58-bbfe-44a8-8fd4-507efb7d47ef
          © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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          Pages: 1
          Categories
          Abstracts
          Poster Abstract

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