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

Daniel A. Pensinger, Matthew T. Aliota, Adam J. Schaenzer, Kyle M. Boldon, Israr Ul H. Ansari, William J.B. Vincent, Benjamin Knight, Michelle L. Reniere, Rob Striker, John Demian Sauer

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26 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)4486-4494
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume58
Issue number8
DOIs
StatePublished - Aug 2014
Externally publishedYes

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    Pensinger, D. A., Aliota, M. T., Schaenzer, A. J., Boldon, K. M., Ansari, I. U. H., Vincent, W. J. B., Knight, B., Reniere, M. L., Striker, R., & Sauer, J. D. (2014). Selective pharmacologic inhibition of a PASTA kinase increases Listeria monocytogenes susceptibility to β-lactam antibiotics. Antimicrobial agents and chemotherapy, 58(8), 4486-4494. https://doi.org/10.1128/AAC.02396-14