New Broad-Spectrum Antibiotics Targeting CoA Synthesis

针对 CoA 合成的新型广谱抗生素

• 批准号: 7052648
• 负责人: Roger Frechette
• 金额: $ 30万
• 依托单位: MAXTHERA, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7052648
• 关键词: Escherichia coli; Staphylococcus aureus; antibacterial agents; bacterial proteins; biological signal transduction; coenzyme A; disease /disorder model; drug discovery /isolation; laboratory mouse; nucleotidyltransferase; pyridoindole

DESCRIPTION (provided by applicant): We intend to develop antibacterials that are different from previous chemical classes and that act on entirely new targets. In prior work we identified a series of tetrahydro-¿-carbolines that are potent inhibitors of a novel, broad-spectrum antibacterial target from E. coli, phosphopantetheine adenyl transferease (PPAT). PPAT catalyzes a rate-limiting step in the Coenzyme A (CoA) biosynthetic pathway in bacteria. We will develop the tetrahydro-¿-carboline series into antibacterial agents with broad-spectrum antibacterial activity and in vivo efficacy. This will be accomplished by using rational and structure-based drug design to increase the antibacterial activity of this series and by applying a battery of biochemical and biological assays to identify compounds that achieve the following specific aims: (1) optimize potency on S. aureus PPAT for broad-spectrum activity; (2) identify compounds with antibacterial activity suitable for in vivo testing; and (3) identify compounds that are effective in an in vivo model of infection. Compounds that exhibit in vivo efficacy, low toxicity, and favorable in vitro ADME properties will progress to lead optimization in Phase II as in vivo-validated leads. Such leads have the potential to become the first antibiotics to target the PPAT enzyme or the CoA biosynthetic pathway and to be effective on antibiotic-resistant strains of a broad spectrum of pathogens. The development of an entirely new chemical class of antibiotics acting on a new target is expected to have an enormous impact on the treatment of resistant infections.

描述（由申请人提供）：我们打算开发与以前的化学类别不同并且作用于全新目标的抗菌药物。在之前的工作中，我们鉴定了一系列四氢-咔啉，它们是大肠杆菌中一种新型广谱抗菌靶点——磷酸泛酸腺苷酸转移酶（PPAT）的有效抑制剂。 PPAT 催化细菌辅酶 A (CoA) 生物合成途径中的限速步骤。我们将把四氢咔啉系列开发成具有广谱抗菌活性和体内功效的抗菌剂。这将通过使用合理和基于结构的药物设计来提高该系列的抗菌活性，并通过应用一系列生化和生物测定来识别实现以下特定目标的化合物来实现：（1）优化金黄色葡萄球菌 PPAT 的广谱活性效力； (2) 鉴定适合体内测试的具有抗菌活性的化合物； (3)鉴定在体内感染模型中有效的化合物。表现出体内功效、低毒性和良好的体外 ADME 特性的化合物将作为体内验证的先导化合物进入 II 期先导化合物优化。此类先导化合物有可能成为第一个针对 PPAT 酶或 CoA 生物合成途径的抗生素，并且对广谱病原体的抗生素耐药菌株有效。作用于新靶点的全新化学类抗生素的开发预计将对耐药感染的治疗产生巨大影响。