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Antimicrob Agents Chemother. 2014 Aug;58(8):4486-94. doi: 10.1128/AAC.02396-14. Epub 2014 May 27.

Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to β-lactam antibiotics.

Author information

  • 1Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 2Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 3Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 4Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
  • 5Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA W. S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA.
  • 6Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA sauer3@wisc.edu.

Abstract

While β-lactam antibiotics are a critical part of the antimicrobial arsenal, they are frequently compromised by various resistance mechanisms, including changes in penicillin binding proteins of the bacterial cell wall. Genetic deletion of the penicillin binding protein and serine/threonine kinase-associated protein (PASTA) kinase in methicillin-resistant Staphylococcus aureus (MRSA) has been shown to restore β-lactam susceptibility. However, the mechanism remains unclear, and whether pharmacologic inhibition would have the same effect is unknown. In this study, we found that deletion or pharmacologic inhibition of the PASTA kinase in Listeria monocytogenes by the nonselective kinase inhibitor staurosporine results in enhanced susceptibility to both aminopenicillin and cephalosporin antibiotics. Resistance to vancomycin, another class of cell wall synthesis inhibitors, or antibiotics that inhibit protein synthesis was unaffected by staurosporine treatment. Phosphorylation assays with purified kinases revealed that staurosporine selectively inhibited the PASTA kinase of L. monocytogenes (PrkA). Importantly, staurosporine did not inhibit a L. monocytogenes kinase without a PASTA domain (Lmo0618) or the PASTA kinase from MRSA (Stk1). Finally, inhibition of PrkA with a more selective kinase inhibitor, AZD5438, similarly led to sensitization of L. monocytogenes to β-lactam antibiotics. Overall, these results suggest that pharmacologic targeting of PASTA kinases can increase the efficacy of β-lactam antibiotics.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PMID:
24867981
[PubMed - in process]
PMCID:
PMC4135996
Free PMC Article
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