Discovery and validation of broadly effective LpxH inhibitors as novel therapeutics against multi-drug resistant Gram-negative pathogens

广泛有效的 LpxH 抑制剂的发现和验证作为针对多重耐药革兰氏阴性病原体的新疗法

• 批准号: 10322657
• 负责人: Pei Zhou
• 金额: $ 45.83万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322657
• 关键词: Acinetobacter baumannii; Aminoglycosides; Anabolism; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Biological Assay; Campylobacter; Carbapenems; Cephalosporins; Chemicals; Clinical; Complex; Dermatitis; Development; Diffusion; Drug Targeting; Drug resistance; Enterobacteriaceae; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Escherichia coli; Extended-spectrum β-lactamase; Fluoroquinolones; Genes; Goals; Gram-Negative Bacteria; Haemophilus influenzae; Health; Helicobacter pylori; Hospitals; Human; Hydrolase; Immunocompromised Host; In Vitro; Infection; Klebsiella pneumoniae; Lead; Lipid A; Lipids; Measurement; Measures; Membrane; Multi-Drug Resistance; Neisseria gonorrhoeae; Organism; Osteomyelitis; Pathway interactions; Patients; Pharmaceutical Preparations; Pseudomonas aeruginosa; Public Health; Refractory; Reporting; Resistance; Respiratory System; Safety; Shigella; Soft Tissue Infections; Structure; Surface; Systemic infection; Tetracyclines; Toxic effect; Urinary tract infection; Validation; Vancomycin resistant enterococcus; X-Ray Crystallography; antimicrobial; antimicrobial drug; assay development; biophysical properties; carbapenem resistance; cheminformatics; clinical development; cytotoxicity; efflux pump; gastrointestinal infection; high throughput screening; in vivo; inhibitor; joint infection; lead optimization; lipid biosynthesis; methicillin resistant Staphylococcus aureus; multi-drug resistant pathogen; novel; novel therapeutics; opportunistic pathogen; pathogen; public health relevance; resistance mechanism; screening; small molecule inhibitor

Project Summary/Abstract An alarming number of Gram-negative nosocomial pathogens have acquired resistance to nearly all currently available antibiotics, making it very difficult to treat patients effectively. Moreover, in the last decade, only a handful of new antimicrobial agents have been introduced, and these have mostly targeted drug-resistant Gram-positive pathogens such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). The goal of this proposal is to develop a high-throughput screening assay to discover and validate small molecule inhibitors of LpxH, an essential enzyme in the lipid A biosynthetic pathway, as novel antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative pathogens.

项目概要/摘要 数量惊人的革兰氏阴性医院病原体已对几乎所有目前的病原体产生了抗药性 可用的抗生素，使得有效治疗患者变得非常困难。而且，在过去十年中，只有 已经推出了少数新的抗菌药物，这些药物大多针对耐药性 革兰氏阳性病原体，例如耐甲氧西林金黄色葡萄球菌 (MRSA) 和耐万古霉素肠球菌 （VRE）。该提案的目标是开发一种高通量筛选方法来发现和验证小分子 LpxH（脂质 A 生物合成途径中的一种必需酶）的分子抑制剂，作为新型抗生素 治疗由多重耐药革兰氏阴性病原体引起的感染。

项目成果

Structure-Activity Relationship of Sulfonyl Piperazine LpxH Inhibitors Analyzed by an LpxE-Coupled Malachite Green Assay.

通过 LpxE 偶联孔雀石绿测定分析磺酰哌嗪 LpxH 抑制剂的构效关系。

• DOI: 10.1021/acsinfecdis.8b00364
• 发表时间: 2019-02-05
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Minhee Lee;Jinshi Zhao;Seung‐Hwa Kwak;J. Cho;M. Lee;R. Gillespie;D. Kwon;Hyunji Lee;Hyun;Qinglin Wu;P. Zhou;Jiyong Hong
• 通讯作者: Jiyong Hong