7OKC

Crystal structure of Escherichia coli LpxA in complex with compound 1

7OKC の概要

• エントリーDOI: 10.2210/pdb7okc/pdb
• 分子名称: Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase, 2-[2-(2-chlorophenyl)sulfanylethanoyl-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]amino]-N-methyl-ethanamide, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: acyltransferase, fatty acids, lipid a, left-handed parallel beta-helix, transferase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28852.20

構造登録者

Ryan, M.D.,Parkes, A.L.,Southey, M.,Andersen, O.A.,Zahn, M.,Barker, J.,DeJonge, B.L.M. (登録日: 2021-05-17, 公開日: 2021-10-06, 最終更新日: 2024-01-31)

主引用文献

Ryan, M.D.,Parkes, A.L.,Corbett, D.,Dickie, A.P.,Southey, M.,Andersen, O.A.,Stein, D.B.,Barbeau, O.R.,Sanzone, A.,Thommes, P.,Barker, J.,Cain, R.,Compper, C.,Dejob, M.,Dorali, A.,Etheridge, D.,Evans, S.,Faulkner, A.,Gadouleau, E.,Gorman, T.,Haase, D.,Holbrow-Wilshaw, M.,Krulle, T.,Li, X.,Lumley, C.,Mertins, B.,Napier, S.,Odedra, R.,Papadopoulos, K.,Roumpelakis, V.,Spear, K.,Trimby, E.,Williams, J.,Zahn, M.,Keefe, A.D.,Zhang, Y.,Soutter, H.T.,Centrella, P.A.,Clark, M.A.,Cuozzo, J.W.,Dumelin, C.E.,Deng, B.,Hunt, A.,Sigel, E.A.,Troast, D.M.,DeJonge, B.L.M.
Discovery of Novel UDP- N -Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa .
J.Med.Chem., 64:14377-14425, 2021

PubMed Abstract: This study describes a novel series of UDP--acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of LpxA with no activity against LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against LpxA (best half-maximal inhibitory concentration (IC) <5 nM) and cellular activity against (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against was maintained (IC > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against .

PubMed: 34569791
DOI: 10.1021/acs.jmedchem.1c00888

実験手法

X-RAY DIFFRACTION (1.84 Å)