6OI9

Crystal Structure of E. coli Biotin Carboxylase Complexed with 7-[3-(aminomethyl)pyrrolidin-1-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine

6OI9 の概要

• エントリーDOI: 10.2210/pdb6oi9/pdb
• 分子名称: Biotin carboxylase, 7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: atp grasp, carboxylase, biotin carboxyl carrier protein and carboxyltransferase, ligase
• 由来する生物種: Escherichia coli UMNK88
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 104080.80

構造登録者

Andrews, L.D.,Kane, T.R.,Dozzo, P.,Haglund, C.M.,Hilderbrandt, D.J.,Linsell, M.S.,Machajewski, T.,McEnroe, G.,Serio, A.W.,Wlasichuk, K.B.,Neau, D.B.,Pakhomova, S.,Waldrop, G.L.,Sharp, M.,Pogliano, J.,Cirz, R.,Cohen, F. (登録日: 2019-04-09, 公開日: 2019-07-31, 最終更新日: 2023-10-11)

主引用文献

Andrews, L.D.,Kane, T.R.,Dozzo, P.,Haglund, C.M.,Hilderbrandt, D.J.,Linsell, M.S.,Machajewski, T.,McEnroe, G.,Serio, A.W.,Wlasichuk, K.B.,Neau, D.B.,Pakhomova, S.,Waldrop, G.L.,Sharp, M.,Pogliano, J.,Cirz, R.T.,Cohen, F.
Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase.
J.Med.Chem., 62:7489-7505, 2019

PubMed Abstract: A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against and , respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in occurs at very low frequencies between 10 and 10. However, resistant isolates had alarmingly high minimum inhibitory concentration shifts (16- to >128-fold) compared to the parent strain. Whole-genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance.

PubMed: 31306011
DOI: 10.1021/acs.jmedchem.9b00625

実験手法

X-RAY DIFFRACTION (2.06 Å)