Propargyl-linked Antifolates Targeting Klebsiella pneumoniae

针对肺炎克雷伯菌的炔丙基连接抗叶酸剂

• 批准号: 8960331
• 负责人: Dennis L. Wright
• 金额: $ 62.75万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 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/8960331
• 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; Extended-spectrum β-lactamase; Fluoroquinolones; Folic Acid Antagonists; Generations; Gram-Positive Bacteria; Half-Life; Health; Healthcare; Human; In Vitro; Infection; Klebsiella pneumonia bacterium; Lead; Link; Mammalian Cell; Maximum Tolerated Dose; Metabolism; 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; course development; design; drug discovery; efficacy evaluation; in vivo; inhibitor/antagonist; mortality; mutant; novel; novel therapeutics; pathogen; resistance mechanism; resistant strain; targeted agent

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.

描述（由申请人提供）：由肠杆菌科引起的感染，主要是革兰氏阴性病原体肺炎克雷伯菌和大肠杆菌，由于对几类抗生素（包括青霉素类、头孢菌素类、碳青霉烯类、氟喹诺酮类和抗叶酸类）的广泛耐药，正变得越来越难以治疗。随着耐药性的出现，对革兰氏阴性病原体有效的药物自然有限，制药行业缺乏抗生素的发现，这些因素结合在一起，产生了对新药发现的迫切需求。在过去的几年里，我们利用基于结构的努力开发了一系列新的丙炔连接的抗叶酸药，这些抗叶酸药能有效抑制必需酶二氢叶酸还原酶（DHFR），对革兰氏阳性和真核病原体有效。此外，这些化合物表现出低的电阻率和良好的物理化学性质。最近，我们发现丙炔连接的抗叶酸盐是培养肺炎克雷伯菌和对抗肺炎克雷伯菌DHFR的有效抑制剂。在这里，我们建议将这类抗叶酸药物扩展为抗致病性肠杆菌科的优秀抗生素。我们提出三个具体目标。在第一个目标中，我们将开发一种抑制剂，它是肺炎克雷伯菌和大肠杆菌DHFR的有效和选择性抑制剂，以及野生型和耐药肠杆菌科（如甲氧苄啶-，ESBL-， KPC-和ndm1 -变体）的有效抑制剂，同时保持低的人体细胞毒性。在第二个目标中，我们将确定野生型和耐甲氧苄啶肠杆菌科DHFR以及人类DHFR的迭代晶体结构，旨在推动有效和选择性化合物的设计。第三个目标将集中在动物研究上：一组有效化合物的初始阶段将从评估对野生型菌株的功效和初始药代动力学参数开始。第二阶段将评估针对一系列表型的疗效以及详细的药代动力学/药效学参数。在本提案的最后，我们期望提供一种高效的，口服的抗叶酸抗生素，用于广泛的肠杆菌科分离物。