Propargyl-linked Antifolates Targeting Klebsiella pneumoniae

针对肺炎克雷伯菌的炔丙基连接抗叶酸剂

基本信息

批准号：
9178633
负责人：
Dennis L. Wright
金额：
$ 69.68万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178633
关键词：
Affect Animals Anti-Bacterial Agents Antibiotics Automobile Driving Bacteremia Bacterial Infections Biological Availability Carbapenems Cells Cephalosporins Clinic Clinical Crystallization Development Dihydrofolate Reductase Drug Industry Drug Kinetics Elements Enterobacteriaceae Enzyme Inhibition Enzymes Escherichia coli Evaluation Extended-spectrum β-lactamase Fluoroquinolones Folic Acid Antagonists Generations Gram-Positive Bacteria Half-Life Healthcare Human In Vitro Infection Klebsiella pneumonia bacterium Lead Link Mammalian Cell Maximum Tolerated Dose Metabolism Mus Oral Organism Pathogenicity Patients Penicillins Pharmacodynamics Phenotype Plasmids Pneumonia Property Proteins Resistance Resistance profile Resolution Sepsis Series Structure Time Toxic effect Treatment Efficacy Trimethoprim Trimethoprim Resistance Urinary tract Urinary tract infection Variant Work analog base beta-Lactamase carbapenemase community setting cost course development design drug discovery efficacy evaluation fluoroquinolone resistance in vivo inhibitor/antagonist mortality mutant novel novel therapeutics pathogen public health relevance resistance mechanism resistant strain targeted agent

项目摘要

DESCRIPTION (provided by applicant): Infections caused by Enterobacteriaceae, primarily the Gram-negative pathogens Klebsiella pneumoniae and Escherichia coli, are becoming increasingly difficult to treat owing to widespread resistance to several classes of antibiotics including penicillins, cephalosporins, carbapenems, fluoroquinolones and antifolates. Along with resistance, the naturally limited array of agents effective against Gram-negative pathogens and the dearth of antibiotic discovery in the pharmaceutical industry combine to create a critical need for new drug discovery. For the past several years, we have used a structure-based effort to develop a novel series of propargyl-linked antifolates that potently inhibit the essential enzyme dihydrofolate reductase (DHFR) and are effective against Gram-positive and eukaryotic pathogens. Additionally, these compounds show low rates of resistance and have good physicochemical properties. Recently, we have discovered that the propargyl-linked antifolates are potent inhibitors of K. pneumoniae in culture and against K. pneumoniae DHFR. Here, we propose to extend this class of antifolates to become excellent antibiotics against pathogenic Enterobacteriaceae. We propose three specific aims. In the first aim, we will develop inhibitors that are potent and selective inhibitors of K. pneumoniae and E. coli DHFR and potent inhibitors of wild-type and resistant Enterobacteriaceae, such as trimethoprim-, ESBL-, KPC- and NDM1-variants while maintaining low human cell toxicity. In the second aim, we will determine iterative crystal structures of wild-type and trimethoprim-resistant Enterobacteriaceae DHFRs as well as human DHFR, intended to drive the design of potent and selective compounds. The third aim will focus on studies in animals: an initial stage with a set of potent compounds begins with the evaluation of efficacy against wild-type strains and initial pharmacokinetic parameters. A second stage will evaluate efficacy against a range of phenotypes along with detailed pharmacokinetic/pharmacodynamic parameters. At the end of this proposal we expect to deliver a highly efficacious, orally available antifolate antibiotic against a broad range of Enterobacteriaceae isolates.

DESCRIPTION (provided by applicant): Infections caused by Enterobacteriaceae, primarily the Gram-negative pathogens Klebsiella pneumoniae and Escherichia coli, are becoming increasingly difficult to treat owing to widespread resistance to several classes of antibiotics including penicillins, cephalosporins, carbapenems, fluoroquinolones and antifolates.除了抵抗外，对革兰氏阴性病原体有效的自然有限的代理和制药行业中抗生素发现的缺乏，共同创造了对新药发现的批判性需求。在过去的几年中，我们已经使用了基于结构的努力来开发一系列新型的proparyl链接抗粉化物，该抗凝血有效地抑制必需酶二氢叶酸酸酯还原酶（DHFR），并有效地抵抗革兰氏阳性和真核病原体。此外，这些化合物显示出较低的抗性速率，并且具有良好的物理化学特性。最近，我们发现，propgyl连接的抗染料是培养物中K.肺炎的有效抑制剂，并且针对K. pneumoniae dhfr。在这里，我们建议扩展这类抗染料，使其成为针对致病肠杆菌科的极好的抗生素。我们提出了三个具体目标。在第一个目标中，我们将开发抑制剂，这些抑制剂对肺炎和大肠杆菌DHFR具有有效和选择性的抑制剂，以及对野生型和抗性肠杆菌科的有效抑制剂，例如trimethoprim-，esbl-，esbl-，kpc-，kpc-和ndm1变量，同时维持低含量的人类细胞毒性。在第二个目标中，我们将确定野生型和抗甲氧苄啶的迭代晶体结构以及旨在推动有效和选择性化合物的设计的人类DHFR。第三个目标将集中于动物的研究：具有一组有效化合物的初始阶段始于评估针对野生型菌株和初始药代动力学参数的功效。第二阶段将评估针对各种表型的功效以及详细的药代动力学/药效参数。在该提案的结尾，我们希望针对广泛的肠杆菌科分离株提供高效的，口服的抗叶酸抗生素。