New Broad-Spectrum Antibiotics Targeting CoA Synthesis

针对 CoA 合成的新型广谱抗生素

• 批准号: 7173849
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173849
• 关键词: 2-Aminopurine; 4' -phosphopantetheine; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Back; Bacteria; Bacterial Antibiotic Resistance; Binding; Biochemical; Biological Assay; Carbolines; Cell Line; Cells; Chemicals; Class; Coenzyme A; Computer Simulation; Development; Docking; Drug Design; Drug Kinetics; Enzymes; Escherichia coli; Exhibits; Genes; Growth; Homologous Gene; Human; In Vitro; Infection; Inhibitory Concentration 50; Lead; Mammalian Cell; Measurement; Measures; Mediating; Modeling; Mus; Pathway interactions; Penetration; Pharmaceutical Preparations; Phase; Predisposition; Property; Qualifying; Rate; Research Personnel; Resistance; Sepsis; Series; Specificity; Staphylococcus aureus; Structure; Techniques; Testing; Toxic effect; Transferase; Work; base; cytotoxicity; falls; high throughput screening; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; intraperitoneal; novel; pathogen; programs; research study; size; small molecule libraries

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)：我们打算开发不同于以前的化学类别的抗菌药，并针对全新的靶点发挥作用。在之前的工作中，我们鉴定了一系列四氢卡宾类化合物，它们是来自大肠杆菌的一种新的广谱抗菌靶标--磷酸铁氨酸腺基转移酶(PPAT)的有效抑制剂。PPAT在细菌中催化辅酶A(CoA)生物合成途径中的限速步骤。我们将把四氢碳啉系列开发成具有广谱抗菌活性和体内疗效的抗菌剂。这将通过使用合理的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分析来确定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的广谱活性的效力；(2)确定适合体内试验的具有抗菌活性的化合物；以及(3)确定在体内感染模型中有效的化合物。表现出体内有效性、低毒性和良好的体外ADME性能的化合物将作为体内验证的线索在第二阶段进行优化。这些先导化合物有可能成为针对PPAT酶或辅酶A生物合成途径的第一批抗生素，并对广泛范围的病原体的抗生素耐药菌株有效。根据新的靶点作用的一种全新的抗生素化学类别的开发，预计将对耐药感染的治疗产生巨大影响。