更新于：2024-11-01

LpxH

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 LpxH 相关的药物

EBL-3599

靶点

LpxH

作用机制

LpxH 抑制剂

在研机构

University of Uppsala

原研机构

University of Uppsala

在研适应症

革兰氏阴性菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

EBL-3647

靶点

LpxH

作用机制

LpxH 抑制剂

在研机构

University of Uppsala

原研机构

University of Uppsala

在研适应症

革兰氏阴性菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 LpxH 相关的临床结果

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100 项与 LpxH 相关的转化医学

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0 项与 LpxH 相关的专利（医药）

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项与 LpxH 相关的文献（医药）

2024-11-01·European Journal of Medicinal Chemistry

Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors

Article

作者: Jones, T. Alwyn ; Jones, T Alwyn ; Lindström, Stefan ; Lola, Daina ; Ottosson, Nina E. ; Ottosson, Nina E ; Klöditz, Katharina ; Lundgren, Bo ; Sandström, Anja ; Mowbray, Sherry L. ; Loza, Einars ; Karlén, Anders ; Mowbray, Sherry L ; Benediktsdottir, Andrea ; Bobileva, Olga ; Cao, Sha ; Sooriyaarachchi, Sanjeewani ; Zamaratski, Edouard ; Kloditz, Katharina ; Hughes, Diarmaid

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.

Genes

Genetic Analysis of the Plasmid-Based Temperature-Lethal Mutant pa1792|lpxH(Ts) in Pseudomonas aeruginosa

Article

作者: Yang, Zhili ; Liu, Jianhua ; Zhang, Haoyang

Many enzymes in the Raetz pathway for lipid A biosynthesis in Escherichia coli are essential. A homologous protein Pa1792|LpxH in Pseudomonas aeruginosa is known to complement the loss of LpxH in E. coli. Genome-wide transposon-insertion sequencing analysis indicates that lpxH is essential in P. aeruginosa. However, genetic analysis of lpxH in P. aeruginosa has not been carried out, partly because the conditional alleles of essential genes are not readily constructed. In this study, we first constructed a plasmid-based temperature-sensitive mutant ΔlpxH/pTS-lpxH or lpxH(Ts) in P. aeruginosa PAO1. Spot-plating assay indicated that lpxH(Ts) was lethal at a restrictive temperature, confirming its essentiality for growth. Microscopic analysis revealed that lpxH(Ts) exhibited an oval-shaped morphology, suggesting that lpxH was required for rod-shape formation. SDS-PAGE and Western blotting analysis showed that lpxH(Ts) failed to synthesize lipid A, consistent with its function in lipid A biosynthesis. Strong expression of lpxH but not the non-homologous isoenzyme lpxI or lpxG impeded growth and caused cell lysis, implying that lpxH-specific cofactors were required for this toxic effect in P. aeruginosa. Together, our results demonstrate that lpxH is essential for lipid A biosynthesis, rod-shaped growth, and viability in P. aeruginosa. We propose that this plasmid-based conditional allele is a useful tool for the genetic study of essential genes in P. aeruginosa.