Discovery of Novel Macrolide Antibiotics

描述（由申请人提供）：抗生素耐药细菌的快速和持续增长代表了必须解决的严重公共卫生威胁经济压力导致积极开展抗菌素研究项目的制药公司数量总体减少，强调了对抗生素新来源的需求这项工作的长远目标是通过发现新的大环内酯类抗生素，通过合理的药物设计直接解决已知的耐药机制，从而满足这一需求。大环内酯类抗生素的作用机制是已知的这些药物结合细菌核糖体，阻止蛋白质合成。最近，各种大环内酯类药物（如红霉素、特红霉素、阿奇霉素）与核糖体亚基结合的晶体结构已经得到解决，为这些化合物如何结合（即与核糖核苷酸残基接触）以及耐药机制如何破坏药物作用提供了有价值的结构见解核糖体自身被修饰的耐药机制对药物化学家来说是一个巨大的挑战为了解决这些特殊的机制并促进化学合成，天然产物结构简化（分子编辑）的范例6将应用于酮内特利霉素。从大环内酯类抗生素红霉素a衍生的第三代半合成药物，自2004年起用于临床。目的包括(1)应用计算机辅助药物设计（CADD）工具，首先评估选定的与野生型和耐药核糖体亚基结合的大环内酯类似物的虚拟文库，以确定最有可能具有生物活性并克服耐药性的候选药物。同时，(2)具有新方法的化学合成将提供获得材料的途径，这些材料将(3)对药物敏感和耐药菌株进行筛选。这将有助于测试复杂大环内酯结构的结构简化将直接解决耐药性而不影响生物活性的假设。另一轮CADD将有助于优化最有希望的候选人。生物测定将衡量这一努力是否成功。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The increase in numbers of antibiotic-resistant bacterial strains represents a serious, global public health issue. The proposed project will address this need by preparing new drugs based on rational drug design with the assistance of computer modeling.