Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus

Infections by Staphylococcus aureushave been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureusby acquisition of the blaand mecoperons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4is covalently engaged with the active-site serine of BlaR. Compound 4potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureusstrains. The combination of 4with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.