Discovery of Novel Macrolide Antibiotics

项目摘要 抗药性细菌的快速和持续上升是对公共健康的严重威胁 必须解决这一问题。1.经济压力已导致总人数减少 拥有积极抗菌素研究计划的制药公司，强调了 2拟议工作的广泛、长期目标是通过以下方式满足这一需要 发现新的大环内酯类抗生素，通过以下方式直接解决已知的耐药性机制 合理的药物设计。 大环内酯类抗生素药物的作用机理是已知的。3这些药物结合细菌 核糖体和阻止蛋白质合成。近年来，各种大环内酯类药物的晶体结构(例如， 红霉素、特利霉素、阿奇霉素)与核糖体亚基结合已被解决，提供 关于这些化合物如何结合(即与核苷酸残基接触)的有价值的结构洞察 以及耐药机制如何破坏药物的作用。4耐药机制中 核糖体本身的修饰对药物化学家来说是一个巨大的挑战。 特殊的机制和便利的化学合成，自然产物结构的范例 简化(分子编辑)6将应用于第三代酮内酯特立红霉素 大环内酯类抗生素红霉素A衍生的半合成药物临床应用 自2004.7以来 目标包括(1)计算机辅助药物设计(CADD)工具的应用，它将首先评估 与野生型和抗性核糖体结合的选定大环内酯类似物的虚拟文库 确定最有可能具有生物活性和克服抗性的候选亚基。在……里面 具有新方法的化学合成将提供获取材料的途径，这将 (3)对药物敏感和耐药菌株进行筛选。这将用来测试 假设复杂大环内酯结构的结构简化将直接解决 在不影响生物活性的情况下进行抗性。另一轮CADD将有助于最大限度地优化 很有前途的候选人。生物检测将衡量这一努力的成功与否。

Project Summary The rapid and incessant rise in antibiotic-resistant bacteria represents a serious public health threat that must be addressed.1 Economic pressures have resulted in an overall decrease in the number of pharmaceutical companies with active antimicrobial research programs, underscoring the need for new sources of antibiotics.2 The broad, long-term goal of the proposed work is to meet this need by discovering novel macrolide antibiotics that directly address known resistance mechanisms by rational drug design. The mechanism of macrolide antibiotic drug action is known.3 These drugs bind the bacterial ribosome and prevent protein synthesis. Recently, crystal structures of various macrolide drugs (e.g., erythromycin, telithromycin, azithromycin) bound to ribosomal subunits have been solved, offering valuable structural insight as to how these compounds bind (i.e., contact with ribonucleotide residues) and how resistance mechanisms undermine drug action.4 Resistance mechanisms in which the ribosome itself is modified represent a formidable challenge to medicinal chemists.5 To address these particular mechanisms and facilitate chemical synthesis, the paradigm of natural product structure simplification (molecular editing)6 will be applied to the ketolide telithromycin, a 3rd generation semisynthetic drug derived from the flagship macrolide antibiotic erythromycin A and used in the clinic since 2004.7 Aims include (1) the application of computer-aided drug design (CADD) tools that will first evaluate a virtual library of selected macrolide analogues bound to both wild-type and resistant ribosomal subunits to determine the candidates most likely to have bioactivity and overcome resistance. In tandem, (2) chemical synthesis featuring novel methodology will provide access to material, which will (3) be screened against drug-susceptible and drug-resistant bacterial strains. This will serve to test the hypothesis that structural simplification of the complex macrolide architecture will directly address resistance without compromising bioactivity. Another round of CADD will serve to optimize the most promising candidates. Bioassays will measure success in this endeavor.