6WII

Crystal structure of the K. pneumoniae LpxH/JH-LPH-41 complex

Summary for 6WII

• Entry DOI: 10.2210/pdb6wii/pdb
• Descriptor: UDP-2,3-diacylglucosamine hydrolase, 5-({[4-({4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]carbamoyl}amino)-N-hydroxypentanamide, MANGANESE (II) ION, ... (6 entities in total)
• Functional Keywords: lpxh, jh-lph-41, lipid a, antibiotic, hydrolase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 30642.05

Authors

Cochrane, C.S.,Cho, J.,Fenton, B.A.,Zhou, P. (deposition date: 2020-04-09, release date: 2020-07-29, Last modification date: 2023-10-18)

Primary citation

Kwak, S.H.,Cochrane, C.S.,Ennis, A.F.,Lim, W.Y.,Webster, C.G.,Cho, J.,Fenton, B.A.,Zhou, P.,Hong, J.
Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.
Bioorg.Chem., 102:104055-104055, 2020

PubMed Abstract: The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.

PubMed: 32663666
DOI: 10.1016/j.bioorg.2020.104055

Experimental method

X-RAY DIFFRACTION (1.85 Å)