Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

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 dev...

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Bibliographic Details
Published in:ChemMedChem 2023-06, Vol.18 (11), p.e202300023-n/a
Main Authors: Kwak, Seung‐Hwa, Skyler Cochrane, C., Cho, Jae, Dome, Patrick A., Ennis, Amanda F., Kim, Jea Hyun, Zhou, Pei, Hong, Jiyong
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibiotics
Bacteria
Bacterial diseases
Calcineurin-like phosphoesterase
Catalytic Domain
Chelation
Dimanganese clusters
Drug Resistance, Multiple, Bacterial
Gram-Negative Bacteria
Health risks
Inhibitors
Lipid A
Lipid A - metabolism
Lipids
LpxH
Metal clusters
Metals
Microbial Sensitivity Tests
Nosocomial infection
Optimization
Pathogens
Pharmacology & Pharmacy
Piperazine
Public health
Pyrophosphatases - metabolism
Structural analysis
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Summary: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. In the lipid A biosynthetic pathway, the enzyme LpxH is a promising antibiotic drug target. In this work, several sulfonyl piperazine LpxH inhibitors were designed and synthesized. Among them, JH‐LPH‐50 shows improved activity against LpxH by chelating the dimanganese cluster in the active site of LpxH.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202300023