7SS6

Structure of Klebsiella LpxH in complex with JH-LPH-45

Summary for 7SS6

• Entry DOI: 10.2210/pdb7ss6/pdb
• Descriptor: UDP-2,3-diacylglucosamine hydrolase, MANGANESE (II) ION, 5-{4-[3-chloro-5-(trifluoromethyl)phenyl]piperazine-1-sulfonyl}-N-[5-(hydroxyamino)-5-oxopentyl]-2,3-dihydro-1H-indole-1-carboxamide, ... (5 entities in total)
• Functional Keywords: lpxh, lipid a, antibiotic, gram-negative bacteria, hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 30589.87

Authors

Cho, J.,Cochrane, C.S.,Zhou, P. (deposition date: 2021-11-09, release date: 2023-04-12, Last modification date: 2023-10-25)

Primary citation

Kwak, S.H.,Skyler Cochrane, C.,Cho, J.,Dome, P.A.,Ennis, A.F.,Kim, J.H.,Zhou, P.,Hong, J.
Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH.
Chemmedchem, 18:e202300023-e202300023, 2023

PubMed Abstract: Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug-resistant Gram-negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese-containing UDP-2,3-diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram-negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first-in-class sulfonyl piperazine LpxH inhibitors, JH-LPH-45 (8) and JH-LPH-50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH-LPH-45 (8) and JH-LPH-50 (13). We expect that further optimization of these proof-of-concept dimanganese-chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug-resistant Gram-negative pathogens.

PubMed: 37014664
DOI: 10.1002/cmdc.202300023

Experimental method

X-RAY DIFFRACTION (1.74 Å)