From Obscurity to Opportunity: LpxH Emerges as a Promising Antibiotic Target in the Battle against Gram-Negative Pathogens.
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2025-11
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The surging crisis of multidrug-resistant Gram-negative pathogens underscores the urgent need for antibiotics with novel mechanisms of action. A promising strategy is to target previously unexploited pathways, such as lipid A biosynthesis. Lipid A functions as the membrane anchor of lipopolysaccharide and constitutes the outer monolayer of the outer membrane of Gram-negative bacteria. LpxH, a Mn2+-dependent phosphoesterase, catalyzes the conversion of UDP-2,3-diacylglucosamine to lipid X, a key precursor in lipid A production. Disruption of this essential step compromises outer membrane integrity, leading to bacterial death, making LpxH an attractive antibiotic target. Since AstraZeneca's discovery of the first small-molecule LpxH inhibitor a decade ago, research has progressed substantially. The development of nonradioactive LpxH activity assays has enabled rapid screening and characterization of inhibitors. Structural and biochemical studies have revealed the architecture of LpxH and dynamic properties of the bound inhibitors, informing structure- and dynamics-based inhibitor design. Notably, recent breakthroughs from academic institutions and pharmaceutical companies have produced LpxH inhibitors with potent antibacterial activity against wild-type Enterobacterales in both in vitro and in vivo models. This review describes the biological role of LpxH and its paralogs, highlights recent advances in assay development and structural analysis, and surveys the current landscape of LpxH-targeting compounds in preclinical development. These collective advances establish LpxH as a novel target in the battle against multidrug-resistant Gram-negative infections and highlight a promising therapeutic opportunity that could reinvigorate the antibiotic pipeline.
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Dome, Patrick A, C Skyler Cochrane, Hannah J Switzer, Hyejin Lee, Pyeonghwa Jeong, Jiyong Hong and Pei Zhou (2025). From Obscurity to Opportunity: LpxH Emerges as a Promising Antibiotic Target in the Battle against Gram-Negative Pathogens. ACS infectious diseases, 11(11). pp. 2993–3008. 10.1021/acsinfecdis.5c00625 Retrieved from https://hdl.handle.net/10161/34031.
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Jiyong Hong
Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies that will allow rapid access to molecular complexity and structural diversity. Through multidisciplinary approaches, including organic synthesis, molecular biology, and cell biology, the cellular components and molecular events that embody cancer, immune response, and GPCR signaling have systematically been explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.
- Synthesis of Natural Products and Study of Mode of Action: We synthesize biologically interesting natural products and explore the modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. Completed target molecules include largazole (a marine natural product with HDAC inhibitory activity), brasilibactin A (a cytotoxic siderophore), manassantins A and B (natural products with anti-HIF-1 activity), and subglutinols A and B (natural products with immunosuppressive activity).
- Development of Novel Synthetic Methodology: We design and develop unique and efficient synthetic strategies which will allow rapid access to molecular complexity and structural diversity. A specific area of interest includes the development of novel methods for the stereoselective synthesis of substituted tetrahydrofurans and tetrahydropyrans.
- Screen of Small Molecule Libraries for Identification of Small Molecule Modulators of Biological Processes: With the advent of combinatorial chemistry and other synthetic technologies, it is feasible to prepare large collections of synthetic organic molecules. These libraries are useful in providing molecules that can be used to probe relevant biological pathways. We are interested in identification of modulators of biological processes, including drug abuse and neurodegenerative diseases.
Through multidisciplinary approaches, the cellular components and molecular events that embody cancer, immune response, and neurodegenerative diseases are systematically explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.
Pei Zhou
The Zhou lab focuses on the elucidation of the structure and dynamics of protein–protein and protein–ligand interactions and their functions in various cellular processes. Our current efforts are directed at enzymes and protein complexes involved in bacterial membrane biosynthesis, translesion DNA synthesis, co-transcriptional regulation, and host-pathogen interactions. Our investigations of these important cellular machineries have led to the development of novel antibiotics and cancer therapeutics, as well as the establishment of new biotechnology adventures.
The Zhou lab integrates a variety of biochemical and biophysical tools, including NMR, X-ray crystallography, cryo-EM, and enzymology. The lab has played a major role in the development and application of innovative NMR technologies, including high-resolution, high-dimensional spectral reconstruction techniques.
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