New Broad-Spectrum Antibiotics Targeting CoA Synthesis

描述（由申请人提供）：我们打算开发不同于以前化学类别的抗菌药物，并对全新的靶标起作用。在之前的工作中，我们发现了一系列四氢碳啉，它们是来自大肠杆菌的新型广谱抗菌靶点磷酸antetheine adenyl transferease （PPAT）的有效抑制剂。PPAT在细菌的辅酶a （CoA）生物合成途径中催化一个限速步骤。我们将开发四氢碳啉系列具有广谱抗菌活性和体内药效的抗菌剂。这将通过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学分析来鉴定达到以下特定目标的化合物来实现：(1)优化对金黄色葡萄球菌PPAT的广谱活性；(2)鉴定出适合体内试验的抗菌活性化合物；(3)鉴定在体内感染模型中有效的化合物。在体内有效、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物在II期进行先导优化。这些线索有可能成为第一种针对PPAT酶或CoA生物合成途径的抗生素，并对广谱病原体的抗生素耐药菌株有效。开发一种全新的化学类抗生素，作用于新的靶标，预计将对耐药感染的治疗产生巨大影响。

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.