Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics

Sang Ho Lee, Lisa Wang Jarantow, Hao Wang, Susan Sillaots, Henry Cheng, Timothy C. Meredith, John Thompson, Terry Roemer

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Abstract

Antibiotic drug resistance among hospital and community acquired methicillin resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current therapeutics. We describe a chemical genetic strategy using antisense interference to broadly identify new drug targets that potentiate the effects of existing antibiotics against both etiological classes of MRSA infection. Further, we describe the resulting chemical genetic interaction networks and highlight the prominent and overlapping target sets that restore MRSA susceptibility to penicillin, cephalosporins, and carbapenems. Pharmacological validation of this approach is the potent synergy between a known inhibitor to a member of this genetic potentiation network (GlmS) and a broad set of β-lactam antibiotics against methicillin resistant Staphylococci. Developing drug-like leads to these targets may serve as rational and effective combination agents when paired with existing β-lactam antibiotics to restore their efficacy against MRSA.

Original languageEnglish (US)
Pages (from-to)1379-1389
Number of pages11
JournalChemistry and Biology
Volume18
Issue number11
DOIs
StatePublished - Nov 23 2011

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Lee, S. H., Jarantow, L. W., Wang, H., Sillaots, S., Cheng, H., Meredith, T. C., Thompson, J., & Roemer, T. (2011). Antagonism of chemical genetic interaction networks resensitize MRSA to β-lactam antibiotics. Chemistry and Biology, 18(11), 1379-1389. https://doi.org/10.1016/j.chembiol.2011.08.015