Therapeutics for drug-resistant bacteria: aryl myxopyronins and arylalkylcarboxamido phloroglucinols

耐药细菌的治疗方法：芳基粘菌素和芳基烷基甲酰胺基间苯三酚

基本信息

批准号：
10394990
负责人：
RICHARD H. EBRIGHT
金额：
$ 65.16万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394990
关键词：
Acinetobacter baumannii Address Adsorption Anti-Bacterial Agents Antibiotics Bacterial Infections Bacterial RNA Binding Sites Cells Chemicals Chemosensitization Complex Crystallization DNA-Directed RNA Polymerase Development Drug Kinetics Drug resistance Enterobacteriaceae Escherichia coli Evaluation Excretory function Exhibits In Vitro Intravenous Klebsiella pneumoniae Lead Lipopolysaccharides Mammalian Cell Maximum Tolerated Dose Membrane Metabolism Multi-Drug Resistance Mus Mycobacterium tuberculosis Oral Pharmaceutical Preparations Pharmacodynamics Phloroglucinol Preparation Procedures Prodrugs Property Pseudomonas aeruginosa Public Health Pyrones Resistance Rifampin Salts Solubility Staphylococcus aureus Structure Structure-Activity Relationship Therapeutic Therapeutic Agents Toxicity Tests Validation Work analog aqueous biodefense chemical function design drug candidate drug resistant bacteria drug-sensitive efficacy testing improved in vivo evaluation indexing innovation lead optimization methicillin resistant Staphylococcus aureus novel novel therapeutics pathogen pathogenic bacteria physical property preclinical evaluation preclinical study scaffold

Acinetobacter baumannii Address Adsorption Anti-Bacterial Agents Antibiotics Bacterial Infections Bacterial RNA Binding Sites Cells Chemicals Chemosensitization Complex Crystallization DNA-Directed RNA Polymerase Development Drug Kinetics Drug resistance Enterobacteriaceae Escherichia coli Evaluation Excretory function Exhibits In Vitro Intravenous Klebsiella pneumoniae Lead Lipopolysaccharides Mammalian Cell Maximum Tolerated Dose Membrane Metabolism Multi-Drug Resistance Mus Mycobacterium tuberculosis Oral Pharmaceutical Preparations Pharmacodynamics Phloroglucinol Preparation Procedures Prodrugs Property Pseudomonas aeruginosa Public Health Pyrones Resistance Rifampin Salts Solubility Staphylococcus aureus Structure Structure-Activity Relationship Therapeutic Therapeutic Agents Toxicity Tests Validation Work analog aqueous biodefense chemical function design drug candidate drug resistant bacteria drug-sensitive efficacy testing improved in vivo evaluation indexing innovation lead optimization methicillin resistant Staphylococcus aureus novel novel therapeutics pathogen pathogenic bacteria physical property preclinical evaluation preclinical study scaffold

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项目摘要

OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020) PROJECT SUMMARY Myxopyronins are α-pyrone antibiotics that function by inhibiting bacterial RNA polymerase through a binding site and mechanism different from those of current antibacterial drugs. In preliminary work, we have performed mode-of-action characterization, lead validation, and initial lead optimization--synthesizing and evaluating more than novel 700 analogs--on myxopyronins. We have identified an exceptionally promising advanced lead: aryl myxopyronin APY281. APY281 exhibits direct activity against drug-sensitive and drug-resistant Gram-positive bacterial pathogens in vitro, potentiated activity against drug-sensitive and drug-resistant Gram-negative bacterial pathogens in vitro, excellent physical properties, excellent intravenous and oral pharmacokinetics in mice, excellent tolerability in mice, potent direct activity against methicillin-resistant Staphylococcus aureus (MRSA) in mice (ED50 = 10 mg/kg iv or po), and potent direct activity against Mycobacterium tuberculosis in mice (ED2log = 200 mg/kg po qd). We also have identified an early lead having a structurally related, but simpler, chemical scaffold: arytalkylcarboxamido phloroglucinol ACP1. ACP1 has the same mode of action, a similar antibacterial profile--including excellent activity against MRSA in mice (ED50 = 2.5 mg/kg iv)--a simpler synthesis, a narrower resistance spectrum, and a lower resistance rate. However, ACP1 has low aqueous solubility. We propose to leverage the crystal structures, structure-activity relationships, and synthetic procedures of our preliminary work in order to design, synthesize, and evaluate improved APY281 analogs having higher efficacy and improved ACP1 analogs having higher efficacy and higher aqueous solubility. In addition, we propose to perform advanced preclinical studies on APY281 and on selected improved APY281 and ACP1 analogs. The primary target pathogens will be drug-resistant and multi-drug-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. The results will enable nomination of at least one development candidate for a first-in-class, systemically active, orally available, therapeutic agent effective against a broad spectrum of drug-sensitive, drug-resistant, and multi-drug-resistant bacterial pathogens.

OMB No. 0925-0001和0925-0002（Rev. 09/17通过03/31/2020批准）项目摘要粘氧蛋白是通过结合抑制细菌RNA聚合酶发挥作用的α-吡咯酮抗生素部位和机制与当前抗菌药物不同。在初步工作中，我们执行了行动方式表征，铅验证和初始铅优化的 - 合成和评估比新颖的700个类似物 - 在粘吡隆蛋白上。我们已经确定了一个异常承诺的高级铅：芳基粘吡喃蛋白APY281。 APY281展览对药物敏感和耐药的革兰氏阳性细菌病原体的直接活性在体外，潜在对药物敏感和耐药的革兰氏阴性细菌病原体的活性在体外，出色的物理特性，出色的静脉注射和口服药代动力学在小鼠中的出色耐受性，潜在的直接在小鼠（ED50 = 10 mg/kg IV或PO）中对耐甲氧西林金黄色葡萄球菌（MRSA）的活性，并且针对小鼠结核分枝杆菌的有效直接活性（ED2LOG = 200 mg/kg PO QD）。我们还确定了具有结构相关但更简单的化学支架的早期铅： Arytalkylcarboxamido phloroglucinol ACP1。 ACP1具有相同的作用方式，一种类似的抗菌轮廓 - 包括针对MRSA的出色活动（ED50 = 2.5 mg/kg IV） - 更简单的合成，A 较窄的电阻频谱和较低的电阻率。但是，ACP1的水溶性低。我们建议利用我们的晶体结构，结构活性关系和合成程序初步工作以设计，合成和评估具有较高效率的APY281类似物并改善具有更高效率和更高水溶性的ACP1类似物。此外，我们建议对APY281和选定改进的APY281和ACP1类似物进行晚期临床前研究。这主要的靶病原体将是耐药和多药抗药性金黄色葡萄球菌，分枝杆菌结核病，铜绿假单胞菌，鲍曼尼杆菌，肺炎，克雷伯氏菌和肺炎大肠杆菌。结果将使至少一名一流的发展候选人提名活跃的，口服的治疗剂有效地针对多种药物敏感，耐药性，和多药耐药细菌病原体。