7K99

Crystal Structure of P. aeruginosa LpxC with N-Hydroxyformamide inhibitor 19

7K99 の概要

• エントリーDOI: 10.2210/pdb7k99/pdb
• 分子名称: UDP-3-O-acyl-N-acetylglucosamine deacetylase, GLYCEROL, (hydroxy{(1S)-1-(methylsulfanyl)-2-[5-({4-[(morpholin-4-yl)methyl]phenyl}ethynyl)-1H-benzotriazol-1-yl]ethyl}amino)methanol, ... (6 entities in total)
• 機能のキーワード: lpxc, hydrolase
• 由来する生物種: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69217.00

構造登録者

Sacco, M.,Chen, Y. (登録日: 2020-09-28, 公開日: 2020-11-25, 最終更新日: 2023-10-18)

主引用文献

Furuya, T.,Shapiro, A.B.,Comita-Prevoir, J.,Kuenstner, E.J.,Zhang, J.,Ribe, S.D.,Chen, A.,Hines, D.,Moussa, S.H.,Carter, N.M.,Sylvester, M.A.,Romero, J.A.C.,Vega, C.V.,Sacco, M.D.,Chen, Y.,O'Donnell, J.P.,Durand-Reville, T.F.,Miller, A.A.,Tommasi, R.A.
N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay.
Bioorg.Med.Chem., 28:115826-115826, 2020

PubMed Abstract: UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.

PubMed: 33160146
DOI: 10.1016/j.bmc.2020.115826

実験手法

X-RAY DIFFRACTION (1.9 Å)