Antagonism of Chemical Genetic Interaction Networks Resensitize MRSA to β-Lactam Antibiotics

SummaryAntibiotic 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.

► Antisense interference-based strategy to identify drug resistance interacting networks
► Chemical-genetic interacting networks antagonize β-lactam resistance in MRSA
► GlmS inhibitor Nva-FMDP is a synergist in combination with β-lactams against MRSA
► β-lactam genetic potentiation maps provide strategy to combat drug resistance