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

Jay Vornhagen1,2,3, Kellie Burnside4, Christopher Whidbey5,6,7

  • 1Department of Pediatric Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195, USA. jay.vornhagen@seattlechildrens.org.

Pathogens (Basel, Switzerland)
|October 28, 2015
PubMed

Insights

Four novel kinase inhibitors enhance susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to beta-lactam antibiotics. These compounds show promise for new MRSA infection therapies with low toxicity in preliminary studies.

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Staphylococcus aureus is a leading cause of recurrent human infections.
  • Methicillin-resistant S. aureus (MRSA) poses a significant therapeutic challenge.
  • MRSA strains lacking serine/threonine kinase (Stk1/PknB) show increased sensitivity to beta-lactam antibiotics.

Purpose of the Study:

  • To identify kinase inhibitors that increase MRSA sensitivity to beta-lactam antibiotics.
  • To evaluate the in vivo toxicity of identified kinase inhibitors.

Main Methods:

  • Screening of 280 low-molecular-weight kinase inhibitors against wild-type MRSA.
  • Testing inhibitor efficacy in combination with sub-lethal beta-lactam concentrations.
  • Assessing compound toxicity in a murine model.

Main Results:

  • Identified four sulfonamide kinase inhibitors (ST085384, ST085404, ST085405, ST085399) that enhance WT MRSA sensitivity to beta-lactams.
  • Inhibitors lacked common toxic structural alerts.
  • No in vivo toxicity observed for ST085384 and ST085405 in mice.

Conclusions:

  • Kinase inhibitors can re-sensitize MRSA to beta-lactam antibiotics.
  • Specific sulfonamide compounds demonstrate potential as adjuncts for MRSA treatment.
  • Further investigation into these kinase inhibitors for MRSA therapeutic strategies is warranted.
Keywords:
antibioticsinhibitionmouseserine/threonine kinasesulfonamides

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