LpxC inhibitors as a novel class of antibiotics against N. gonorrhoeae

LpxC 抑制剂作为一类新型抗淋病奈瑟菌抗生素

• 批准号: 8440335
• 负责人: ROBERT A NICHOLAS
• 金额: $ 68.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440335
• 关键词: Address; Anabolism; Antibiotic Therapy; Antibiotics; Benchmarking; Biochemistry; Biological Assay; Case Study; Ceftriaxone; Data; Dependency; Development; Dose; Drug Kinetics; Ectopic Pregnancy; Effectiveness; Enzymatic Biochemistry; Enzymes; Escherichia coli; Evaluation; Event; Excretory function; Fluoroquinolones; Generations; Genetic; Goals; Gonorrhea; Gram-Negative Bacteria; HIV; Human; Immune system; In Vitro; Infection; Infertility; Investigational New Drug Application; Ion Channel; Lead; Lipid A; Metabolism; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Pathogenesis; Pathway interactions; Pelvic Inflammatory Disease; Penicillins; Pharmaceutical Chemistry; Pharmacodynamics; Property; Pseudomonas aeruginosa; Public Health; Reporting; Research; Resistance; Resistance development; Route; Sexually Transmitted Diseases; Signal Transduction; Staging; Structure-Activity Relationship; Testing; Tetracyclines; Time; Toxic effect; Toxicity Tests; United States; absorption; bacterial resistance; bactericide; base; chemical synthesis; cost effective; design; drug candidate; hydroxamate; improved; in vitro activity; in vivo; inhibitor/antagonist; meetings; metalloenzyme; mouse model; novel; process optimization; public health relevance; resistance mechanism; resistant strain; screening; stem; structural biology; transmission process

DESCRIPTION (provided by applicant): Neisseria gonorrhoeae is the etiologic agent of the sexually transmitted infection, gonorrhea. Antibiotics are the mainstay in treating infections, but widespread resistance in N. gonorrhoeae, most notably emerging resistance to ceftriaxone, may soon result in strains that are untreatable with current antibiotics. Thus, new antibiotics against novel targets are desperately needed to stem the tide of resistant bacteria that are becoming a major threat to public health. The goal of this proposal is to optimize inhibitors of LpxC, an essential enzyme in the lipid A biosynthetic pathway, for treatment of N. gonorrhoeae infections. Preliminary data demonstrate that LpxC inhibitors are bactericidal for N. gonorrhoeae and are largely unaffected by established resistance mechanisms. Further development of these novel compounds will be achieved by (1) lead optimization of LpxC inhibitors, (2) evaluation of pharmacokinetic and pharmacodynamic properties of lead compounds, and (3) evaluation of antibiotic efficacies in a mouse model of infection. At the completion of this project, we anticipate having one or more LpxC inhibitors with good pharmacokinetic and pharmacodynamic properties that are potent and efficacious against N. gonorrhoeae both in vitro and in vivo. These studies would meet a number of benchmarks required for assembling an investigational new drug application to the FDA for approval of a new class of antibiotics for treatment of N. gonorrhoeae and other Gram-negative infections.

描述（由申请人提供）：淋病奈瑟菌是性传播感染淋病的病原体。抗生素是治疗感染的主要药物，但耐药性在N。淋病，最显著的是对头孢曲松的耐药性，可能很快就会产生目前抗生素无法治疗的菌株。因此，迫切需要针对新靶点的新抗生素来阻止耐药细菌的浪潮，这些细菌正在成为公共卫生的主要威胁。本提案的目标是优化LpxC（脂质A生物合成途径中的一种重要酶）的抑制剂，用于治疗N。淋病感染初步数据表明，LpxC抑制剂对N.淋病，并在很大程度上不受既定的耐药机制。这些新化合物的进一步开发将通过以下方式实现：（1）LpxC抑制剂的先导优化，（2）先导化合物的药代动力学和药效学性质的评价，以及（3）在小鼠感染模型中抗生素功效的评价。在该项目完成时，我们预计将获得一种或多种具有良好药代动力学和药效学特性的LpxC抑制剂，这些抑制剂对N.淋病在体外和体内。这些研究将满足向FDA提交研究性新药申请所需的一些基准，以批准一类新的抗生素用于治疗N。淋病和其他革兰氏阴性菌感染。