Discovery of Novel Macrolide Antibiotics

描述（申请人提供）：抗药性细菌的迅速和不断增加是一个严重的公共卫生威胁，必须加以解决。1经济压力导致具有积极的抗菌剂研究项目的制药公司数量总体减少，强调了对新的抗菌剂来源的需求。所提出的工作的长期目标是通过发现新的大环内酯类抗生素来满足这一需求，所述新的大环内酯类抗生素通过合理的药物设计来直接解决已知的耐药机制。大环内酯类抗生素的作用机制是已知的。3这些药物结合细菌核糖体并阻止蛋白质合成。最近，各种大环内酯类药物的晶体结构（例如，红霉素、泰利霉素、阿奇霉素）结合到核糖体亚基上，提供了关于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。4其中核糖体本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。5为了解决这些特殊机制并促进化学合成，天然产物结构简化的范例（分子编辑）6将应用于酮内酯泰利霉素，第三代半合成药物，衍生自旗舰大环内酯类抗生素红霉素A，自2004年起用于临床。7目的包括（1）计算机辅助药物设计（CADD）工具的应用，该工具将首先评估与野生型和耐药核糖体亚基结合的选定大环内酯类似物的虚拟库，以确定最有可能具有生物活性并克服耐药性的候选物。与此同时，（2）以新方法为特征的化学合成将提供获得材料的途径，这些材料将（3）针对药物敏感和耐药菌株进行筛选。这将用于检验复杂大环内酯结构的结构简化将直接解决耐药性而不损害生物活性的假设。另一轮CADD将用于优化最有希望的候选人。生物测定将衡量这一奋进的成功。 公共卫生相关性：耐药性细菌菌株数量的增加代表了一个严重的全球公共卫生问题。拟议的项目将通过在计算机建模的协助下基于合理药物设计制备新药来满足这一需求。

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.