8C0S

Crystal structure of S. aureus BlaR1 sensor domain in complex with an imidazole inhibitor

Summary for 8C0S

• Entry DOI: 10.2210/pdb8c0s/pdb
• Related: 8C0P
• Descriptor: Regulatory protein BlaR1, 3-[[2,4-bis(trifluoromethyl)phenyl]methyl]-5-(hydroxymethyl)-1~{H}-imidazole-2-thione (3 entities in total)
• Functional Keywords: antibiotic resistance, b-lactam sensor, mrsa, signaling protein
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 2
• Total formula weight: 60253.44

Authors

Miguel-Ruano, V.,Hermoso, J.A. (deposition date: 2022-12-19, release date: 2024-07-10, Last modification date: 2024-09-04)

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

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: 39060390
DOI: 10.1038/s41589-024-01688-0

Experimental method

X-RAY DIFFRACTION (2 Å)