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

• 批准号: 10613893
• 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
• 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/10613893
• 关键词: Acinetobacter baumannii; Adsorption; Anti-Bacterial Agents; Antibiotics; Bacterial Infections; Bacterial RNA; Binding Sites; Cells; Chemicals; Chemosensitization; Complex; DNA-Directed RNA Polymerase; Development; Drug Kinetics; Drug resistance; Early identification; 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; 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

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 编号 0925-0001 和 0925-0002（修订版 09/17 已批准至 2020 年 3 月 31 日） 项目概要 粘菌素是 α-吡喃酮抗生素，通过结合抑制细菌 RNA 聚合酶发挥作用。 其作用位点和作用机制与现有抗菌药物不同。 在前期工作中，我们进行了作用模式表征、先导化合物验证和初始先导化合物 对 myxopyronins 进行优化——合成和评估超过 700 种新型类似物。 我们已经确定了一种非常有前途的先进先导化合物：芳基粘菌素 APY281。 APY281展品 体外对药物敏感和耐药革兰氏阳性细菌病原体的直接活性增强 对药物敏感和耐药的革兰氏阴性细菌病原体具有体外活性，优异的物理性能 特性，在小鼠中具有出色的静脉注射和口服药代动力学，在小鼠中具有出色的耐受性，有效的直接作用 对小鼠中耐甲氧西林金黄色葡萄球菌 (MRSA) 的活性（ED50 = 10 mg/kg 静脉注射或口服），以及 对小鼠中的结核分枝杆菌具有有效的直接活性（ED2log = 200 mg/kg po qd）。 我们还发现了一种早期先导化合物，其具有结构相关但更简单的化学支架： 芳基烷基甲酰胺基间苯三酚 ACP1。 ACP1具有相同的作用方式，相似的抗菌作用 概况 - 包括对小鼠中 MRSA 的优异活性（ED50 = 2.5 mg/kg iv） - 更简单的合成， 耐药谱更窄，耐药率更低。然而，ACP1的水溶性较低。 我们建议利用我们的晶体结构、结构-活性关系和合成程序 设计、合成和评估具有更高功效的改进APY281类似物的前期工作 以及具有更高功效和更高水溶性的改良ACP1类似物。此外，我们建议 对 APY281 以及选定的改进 APY281 和 ACP1 类似物进行高级临床前研究。这 主要目标病原体将是耐药和多重耐药金黄色葡萄球菌， 结核分枝杆菌、铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌和 大肠杆菌。 结果将能够提名至少一名开发候选者，以系统地进行一流的开发 活性、口服、有效对抗广谱药物敏感、耐药、 和多重耐药细菌病原体。