8CF3

Crystal structure of S. aureus BlaR1 sensor domain in complex with cefepime

8CF3 の概要

• エントリーDOI: 10.2210/pdb8cf3/pdb
• 関連するPDBエントリー: 8C0P 8C0S
• 分子名称: Regulatory protein BlaR1, Cefepime (open) (3 entities in total)
• 機能のキーワード: antibiotic resistance, beta-lactam sensor of staphylococcus aureus, mrsa, signaling protein
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 59885.44

構造登録者

Miguel-Ruano, V.,Hermoso, J.A. (登録日: 2023-02-02, 公開日: 2024-09-04, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.52 Å)