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Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH
Seung-Hwa Kwak1,2, C Skyler Cochrane1, Jae Cho3,4
1Department of Chemistry, Duke University, Durham, NC 27708, USA.
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.
Insights
New sulfonyl piperazine compounds targeting LpxH offer a novel approach to combat multidrug-resistant Gram-negative infections. These compounds chelate the enzyme
Area of Science:
- Medicinal Chemistry
- Microbiology
- Structural Biology
Background:
- Multidrug-resistant Gram-negative bacterial infections pose a significant public health threat.
- No new classes of antibiotics for Gram-negative pathogens have been approved in 50 years, highlighting an urgent need for novel treatments.
- Targeting previously unexploited pathways is crucial for developing effective antibiotics against resistant pathogens.
Purpose of the Study:
- To develop novel sulfonyl piperazine compounds targeting LpxH, a key enzyme in the lipid A biosynthetic pathway.
- To design inhibitors that chelate the active site dimanganese cluster of K. pneumoniae LpxH (KpLpxH).
- To validate the structural basis and inhibitory potential of these novel compounds.
Main Methods:
- Investigated a series of sulfonyl piperazine compounds.
- Utilized structural analysis of inhibitors complexed with KpLpxH.
- Developed and structurally validated new inhibitors, JH-LPH-45 and JH-LPH-50.
- Assessed the chelation of the active site dimanganese cluster.
Main Results:
- Developed first-in-class sulfonyl piperazine LpxH inhibitors, JH-LPH-45 and JH-LPH-50.
- Demonstrated that these compounds effectively chelate the active site dimanganese cluster of KpLpxH.
- Observed that dimanganese cluster chelation significantly enhances inhibitor potency.
Conclusions:
- JH-LPH-45 and JH-LPH-50 represent a promising new class of LpxH inhibitors.
- Dimanganese chelation is a viable strategy for improving the potency of LpxH inhibitors.
- Further optimization could lead to potent antibiotics against multidrug-resistant Gram-negative pathogens.
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