8C0P
Crystal structure of S. aureus BlaR1 sensor domain in complex with a boronate inhibitor
Summary for 8C0P
| Entry DOI | 10.2210/pdb8c0p/pdb |
| Descriptor | Regulatory protein BlaR1, [1-[[2,4-bis(trifluoromethyl)phenyl]methyl]benzimidazol-2-yl]sulfanylmethyl-$l^{3}-oxidanyl-bis(oxidanyl)boron (3 entities in total) |
| Functional Keywords | antibiotic resistance, beta-lactam sensor of staphylococcus aureus, mrsa, signaling protein |
| Biological source | Staphylococcus aureus More |
| Total number of polymer chains | 2 |
| Total formula weight | 60443.21 |
| Authors | Miguel-Ruano, V.,Jimenez-Faraco, E.,Hermoso, J.A. (deposition date: 2022-12-19, release date: 2024-07-10, Last modification date: 2024-11-06) |
| Primary citation | Nguyen, V.T.,Birhanu, B.T.,Miguel-Ruano, V.,Kim, C.,Batuecas, M.,Yang, J.,El-Araby, A.M.,Jimenez-Faraco, E.,Schroeder, V.A.,Alba, A.,Rana, N.,Sader, S.,Thomas, C.A.,Feltzer, R.,Lee, M.,Fisher, J.F.,Hermoso, J.A.,Chang, M.,Mobashery, S. Restoring susceptibility to beta-lactam antibiotics in methicillin-resistant Staphylococcus aureus. Nat.Chem.Biol., 2024 Cited by PubMed Abstract: 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. PubMed: 39060390DOI: 10.1038/s41589-024-01688-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.97 Å) |
Structure validation
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