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

管理及预算局编号0925-0001及0925-0002(截至2020年3月31日获批准的09/17修订版) 项目总结 粘比诺宁是一种α-吡喃酮类抗生素，通过结合抑制细菌核糖核酸聚合酶发挥作用。 作用部位和作用机制与目前的抗菌药物不同。 在前期工作中，我们执行了行动模式表征、线索验证和初始线索 优化--合成和评估700多个新的类似物--关于粘比罗宁。 我们已经确定了一种非常有希望的先进先导：芳基粘比罗宁APY281。APY281展品 体外对药物敏感和耐药的革兰氏阳性细菌的直接活性增强 体外对药物敏感和耐药的革兰氏阴性细菌的活性，良好的物理性能 在小鼠体内的静脉和口服药代动力学良好，在小鼠中的耐受性良好，有效的直接 对小鼠耐甲氧西林金黄色葡萄球菌(MRSA)的活性(ED50=10 mg/kg iv或po)，以及 对小鼠结核分枝杆菌有较强的直接抑制作用(ED2log=200 mg/kg，po，qd)。 我们还发现了一种早期的铅，它具有结构上相关但更简单的化学支架： 芳基羧胺基间苯三酚ACP1。ACP1具有相同的作用模式，具有相似的抗菌作用 Profile--包括在小鼠中对MRSA的优异活性(ED50=2.5 mg/kg iv)--一种更简单的合成方法，a 更窄的阻力谱，更低的阻抗率。然而，ACP1的水溶解度较低。 我们建议利用我们的晶体结构、结构-活性关系和合成过程 为设计、合成和评估具有更高疗效的改进的APY281类似物所做的前期工作 改进的ACP1类似物具有更高的药效和更高的水溶解度。此外，我们建议 对APY281以及选定的改进的APY281和ACP1类似物进行高级临床前研究。这个 主要目标病原体将是耐药和多重耐药的金黄色葡萄球菌， 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 大肠埃希菌。 结果将使至少一个开发候选人的提名成为一流的，系统的 活性的，口服的，对广谱的药物敏感，耐药， 和多重耐药的细菌病原体。

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.