8E7Q

Crystal Structure of FosB from Bacillus cereus with Zinc and 2-Phosphonopropionic acid

8E7Q の概要

• エントリーDOI: 10.2210/pdb8e7q/pdb
• 分子名称: Metallothiol transferase FosB, (2S)-2-phosphonopropanoic acid, FORMIC ACID, ... (6 entities in total)
• 機能のキーワード: inhibitor, 2-phosphonopropionic acid, transferase
• 由来する生物種: Bacillus cereus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33510.54

構造登録者

Travis, S.,Tsodikov, O.V.,Garneau-Tsodikova, S.,Thompson, M.K. (登録日: 2022-08-24, 公開日: 2023-06-14, 最終更新日: 2023-10-25)

主引用文献

Travis, S.,Green, K.D.,Thamban Chandrika, N.,Pang, A.H.,Frantom, P.A.,Tsodikov, O.V.,Garneau-Tsodikova, S.,Thompson, M.K.
Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus.
Rsc Med Chem, 14:947-956, 2023

PubMed Abstract: Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as , one of the leading pathogens in deaths associated with AMR. gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from by applying high-throughput screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in . Our results will inform future studies on inhibitor design for the FosB enzymes.

PubMed: 37252104
DOI: 10.1039/d3md00113j

実験手法

X-RAY DIFFRACTION (1.9 Å)