Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH
- Department of Chemistry Duke University Durham NC 27708 USA; Current address: Ambagon Therapeutics Inc. 953 Indiana Street San Francisco CA 94107 USA
- Department of Chemistry Duke University Durham NC 27708 USA
- Department of Biochemistry Duke University School of Medicine Durham NC 27710 USA; Current address: Epigenetics &, Stem Cell Biology Laboratory National Institute of Environmental Health Sciences Durham NC 27709 USA
- Department of Chemistry Duke University Durham NC 27708 USA; Department of Biochemistry Duke University School of Medicine Durham NC 27710 USA
- Department of Chemistry Duke University Durham NC 27708 USA; Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham NC 27710 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 withK. pneumoniaeLpxH (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 ofKpLpxH. 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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC02-06CH11357
- OSTI ID:
- 2423379
- Journal Information:
- ChemMedChem, Journal Name: ChemMedChem Journal Issue: 11 Vol. 18; ISSN 1860-7179
- Publisher:
- ChemPubSoc Europe
- Country of Publication:
- United States
- Language:
- English