Kinase inhibitors that increase the sensitivity of methicillin resistant Staphylococcus aureus to β-lactam antibiotics

Jay Vornhagen, Kellie Burnside, Christopher Whidbey, Jessica Berry, Xuan Qin, Lakshmi Rajagopal

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)708-721
Number of pages14
JournalPathogens
Volume4
Issue number4
DOIs
StatePublished - Oct 22 2015
Externally publishedYes

Keywords

  • Antibiotics
  • Inhibition
  • Mouse
  • Serine/threonine kinase
  • Sulfonamides

ASJC Scopus subject areas

  • Immunology and Allergy
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Microbiology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Kinase inhibitors that increase the sensitivity of methicillin resistant Staphylococcus aureus to β-lactam antibiotics'. Together they form a unique fingerprint.

Cite this