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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：
8616446
负责人：
Amy C. Anderson
金额：
$ 56.22万
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/8616446
关键词：
Affect Animals Anti-Bacterial Agents Antibiotics Automobile Driving Bacteremia Bacterial Infections Binding Biological Availability Carbapenems Cells Cephalosporins Clinic Clinical Development Dihydrofolate Reductase Drug Industry Drug Kinetics Elements Enterobacteriaceae Enzyme Inhibition Enzymes Escherichia coli Evaluation Fluoroquinolones Folic Acid Antagonists Generations Gram-Positive Bacteria Half-Life Healthcare Human In Vitro Infection Inhibitory Concentration 50 Klebsiella pneumonia bacterium Lead Link Mammalian Cell Maximum Tolerated Dose Metabolism Metric Mus Oral Organism Patients Penicillins Pharmacodynamics Phenotype Plasmids Pneumonia Property Proteins Resistance Resistance profile Resolution Sepsis Series Staging Structure Therapeutic Time Toxic effect Trimethoprim Trimethoprim Resistance Urinary tract Urinary tract infection Variant Work analog base beta-Lactamase community setting cost design drug discovery efficacy evaluation in vivo inhibitor/antagonist mortality mutant novel pathogen public health relevance resistance mechanism resistant strain

项目摘要

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.

由肠杆菌科引起的感染，主要是革兰氏阴性病原体克雷伯氏菌