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

LpxC 抑制剂作为一类针对淋病奈瑟菌的新型抗生素

• 批准号: 8248688
• 负责人: ROBERT A NICHOLAS
• 金额: $ 74.17万
• 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/8248688
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: The sexually transmitted infection (STI) gonorrhea, caused by the Gram-negative bacterium, Neisseria gonorrhoeae, is the second most common STI in the U.S., with over 350,000 cases reported in 2007. N. gonorrhoeae is a major cause of pelvic inflammatory disease, can increase the possibility of ectopic pregnancy, and is associated with an increased rate of transmission of HIV. Historically, N. gonorrhoeae has become resistant to nearly all of the antibiotics that have been used to treat infections, including penicillin, tetracycline, and fluoroquinolones. The minimum inhibitory concentrations (MICs) of the sole antibiotic recommended for treatment of gonococcal infections, ceftriaxone, have increased rapidly in the last decade, and it is only a matter of time before the emergence of fully resistant strains of N. gonorrhoeae renders all of the current treatment options obsolete. This proposal addresses this unmet global public health need by optimizing inhibitors of LpxC, which catalyzes an essential step in lipid A biosynthesis to treat gonococcal infections, including those caused by multidrug-resistant strains. Successful completion of this proposal has the potential to develop a new class of antibiotics that target an unexploited essential pathway in Gram-negative bacteria.

描述(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，但淋球菌中广泛存在的耐药性，最明显的是对头孢曲松的耐药性，可能很快就会导致目前的抗生素无法治愈的菌株。因此，迫切需要针对新靶点的新抗生素来阻止耐药性细菌的浪潮，这些细菌正在成为对公共健康的主要威胁。这项建议的目标是优化LpxC的抑制剂，LpxC是脂质A生物合成途径中的一种关键酶，用于治疗淋病奈瑟菌感染。初步数据表明，LpxC抑制剂对淋球菌具有杀菌作用，基本上不受既定耐药机制的影响。这些新化合物的进一步开发将通过(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估，以及(3)在小鼠感染模型中的抗生素效果评估来实现。在该项目完成后，我们预计将有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，在体外和体内都能有效地对抗淋病奈瑟菌。这些研究将达到向FDA提交的研究性新药申请所需的一些基准，以批准用于治疗淋球菌和其他革兰氏阴性感染的新型抗生素。 公共卫生相关性：性传播感染(STI)淋病，由革兰氏阴性菌淋球菌引起，是美国第二常见的STI，2007年报告了超过350,000例。淋球菌是盆腔炎的主要原因，可增加异位妊娠的可能性，并与艾滋病毒传播率增加有关。从历史上看，淋球菌对几乎所有用于治疗感染的抗生素都产生了抗药性，包括青霉素、四环素和氟喹诺酮类药物。推荐用于治疗淋球菌感染的唯一抗生素头孢曲松的最低抑菌浓度(MIC)在过去十年中迅速增加，淋球菌完全耐药株的出现使目前所有的治疗选择过时只是个时间问题。这项建议通过优化LpxC的抑制剂来满足这一未得到满足的全球公共卫生需求，LpxC的抑制剂催化了类脂A生物合成的关键步骤，以治疗淋球菌感染，包括由多重耐药菌株引起的感染。这项提案的成功完成有可能开发一种新的抗生素类别，针对革兰氏阴性细菌中尚未开发的基本途径。