Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme with zinc ions as cofactors and is a key enzyme in the essential structural outer membrane lipid A synthesis commitment step of gram-negative bacteria. As LpxC is extremely homologous among different Gram-negative bacteria, it is conserved in almost all gram-negative bacteria, which makes LpxC a promising target. LpxC inhibitors have been reported extensively in recent years, such as PF-5081090 and CHIR-090 were found to have broad-spectrum antibiotic activity against P. aeruginosa and E. coli. They are mainly classified into hydroxamate inhibitors and non-hydroxamate inhibitors based on their structure, but no LpxC inhibitors have been marketed due to safety and activity issues. This review, therefore, focuses on small molecule inhibitors of LpxC against gram-negative pathogenic bacteria and covers recent advances in LpxC inhibitors, focusing on their structural optimization process, structure-activity relationships, and future directions, with the aim of providing ideas for the development of LpxC inhibitors and clinical research.
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- Parkinson's disease (PD) is a major neurodegenerative disorder and recent studies link its pathogenesis to imbalances in gut microbiota, particularly involving Gram-negative bacteria and their endotoxin, lipopolysaccharide (LPS), which triggers inflammatory responses in the gut and brain.
- Recent findings suggest there is a connection between LPS, alpha-synuclein, and toll-like receptor 4 (TLR4), indicating a mechanism that might exacerbate inflammation and neurodegeneration in PD, warranting further research.
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