| Autor: |
Nguyen, Van T., Birhanu, Biruk T., Miguel-Ruano, Vega, Kim, Choon, Batuecas, Mayte, Yang, Jingdong, El-Araby, Amr M., Jiménez-Faraco, Eva, Schroeder, Valerie A., Alba, Alejandra, Rana, Neha, Sader, Safaa, Thomas, Caitlyn A., Feltzer, Rhona, Lee, Mijoon, Fisher, Jed F., Hermoso, Juan A., Chang, Mayland, Mobashery, Shahriar |
| Zdroj: |
Nature Chemical Biology; 20240101, Issue: Preprints p1-8, 8p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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