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Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to β-Lactam Antibiotics

by Jay Vornhagen 1,2,3,†, Kellie Burnside 1,†,‡, Christopher Whidbey 1,2,3,†,§, Jessica Berry 2, Xuan Qin 2 and Lakshmi Rajagopal 1,2,3,*
1
Department of Pediatric Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195, USA
2
Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA
3
Department of Global Health, University of Washington School of Public Health, Seattle, WA 98195, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: LabCorp Clinical Trials, Seattle, WA 98109, USA.
§
Current address: Pacific Northwest National Laboratory, Richland, WA 99354, USA.
Academic Editor: Rachel McLoughlin
Pathogens 2015, 4(4), 708-721; https://doi.org/10.3390/pathogens4040708
Received: 24 August 2015 / Revised: 16 October 2015 / Accepted: 20 October 2015 / Published: 22 October 2015
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
Staphylococcus aureus are Gram-positive bacteria that are the leading cause of recurrent infections in humans that include pneumonia, bacteremia, osteomyelitis, arthritis, endocarditis, and toxic shock syndrome. The emergence of methicillin resistant S. aureus strains (MRSA) has imposed a significant concern in sustained measures of treatment against these infections. Recently, MRSA strains deficient in expression of a serine/threonine kinase (Stk1 or PknB) were described to exhibit increased sensitivity to β-lactam antibiotics. In this study, we screened a library consisting of 280 drug-like, low-molecular-weight compounds with the ability to inhibit protein kinases for those that increased the sensitivity of wild-type MRSA to β-lactams and then evaluated their toxicity in mice. We report the identification of four kinase inhibitors, the sulfonamides ST085384, ST085404, ST085405, and ST085399 that increased sensitivity of WT MRSA to sub-lethal concentrations of β-lactams. Furthermore, these inhibitors lacked alerting structures commonly associated with toxic effects, and toxicity was not observed with ST085384 or ST085405 in vivo in a murine model. These results suggest that kinase inhibitors may be useful in therapeutic strategies against MRSA infections. View Full-Text
Keywords: serine/threonine kinase; sulfonamides; antibiotics; inhibition; mouse serine/threonine kinase; sulfonamides; antibiotics; inhibition; mouse
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Vornhagen, J.; Burnside, K.; Whidbey, C.; Berry, J.; Qin, X.; Rajagopal, L. Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to β-Lactam Antibiotics. Pathogens 2015, 4, 708-721.

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