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.

项目摘要/摘要 目前，数量惊人的革兰氏阴性医院内病原菌已对几乎所有 可获得的抗生素，使有效治疗患者变得非常困难。此外，在过去的十年中，只有一个 已经推出了几种新的抗菌剂，这些抗菌剂大多针对抗药性 革兰氏阳性病原菌，如耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌 (Vre)。这项提案的目标是开发一种高通量筛查试验，以发现和验证小分子 LpxH的分子抑制剂，LpxH是脂质A生物合成途径中的一种关键酶，作为治疗癌症的新型抗生素 多重耐药革兰氏阴性菌感染的治疗。

项目成果

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

• DOI: 10.1021/acsinfecdis.8b00364
• 发表时间: 2019-02
• 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-Ju Park;Qinglin Wu;P. Zhou;Jiyong Hong