Van T. Nguyen, Biruk T. Birhanu, Vega Miguel-Ruano, Choon Kim, Mayte Batuecas, Jingdong Yang, Amr M. El-Araby, Eva Jiménez-Faraco, Valerie A. Schroeder, Alejandra Alba, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Juan A. Hermoso, Mayland Chang & Shahriar Mobashery
Nat Chem Biol 2024
https://www.nature.com/articles/s41589-024-01688-0
Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. 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 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.
