Discovery of Novel Macrolide Antibiotics

新型大环内酯类抗生素的发现

• 批准号: 8089259
• 负责人: RODRIGO B ANDRADE
• 金额: $ 34.64万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089259
• 关键词: Address; Affinity; Antibiotic Resistance; Antibiotics; Architecture; Azithromycin; Bacteria; Bacterial Antibiotic Resistance; Binding; Biological; Biological Assay; Biological Factors; Chemistry; Clinic; Complex; Computer Assisted; Computer Simulation; Drug Design; Drug Kinetics; Drug effect disorder; Drug resistance; Economics; Erythromycin; Escherichia coli; Future; Generations; Goals; Gram-Positive Bacteria; Guanosine; Hydrogen; Ketolides; Laboratories; Libraries; Ligands; Macrolide Antibiotics; Macrolides; Measures; Methodology; Methods; Minimum Inhibitory Concentration measurement; Molecular; Molecular Conformation; Mutation; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Property; Protein Biosynthesis; Public Health; Research; Resistance; Resources; Ribonucleotides; Ribosomal RNA; Ribosomes; Role; Route; Scheme; Side; Source; Structure; Testing; Virtual Library; Work; analog; antimicrobial; attenuation; bacterial resistance; bactericide; base; chemical synthesis; design; desosamine; efficacy testing; in vivo; insight; interest; meetings; methicillin resistant Staphylococcus aureus; methyl group; novel; pressure; prevent; programs; public health relevance; pyranose; research clinical testing; resistance mechanism; scaffold; success; telithromycin; tool

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.

描述(由申请人提供)：抗药性细菌的快速和持续上升是一个必须解决的严重公共健康威胁。1经济压力已导致具有积极抗菌素研究计划的制药公司的总体数量减少，强调了对新的抗生素来源的需求。2拟议工作的广泛、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，这些抗生素通过合理的药物设计直接解决已知的耐药性机制。大环内酯类抗菌药物的作用机制已知。3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、泰利霉素、阿奇霉素)与核糖体亚基结合的晶体结构已被解决，这为了解这些化合物如何结合(即，与核糖核苷酸残基接触)以及耐药性机制如何破坏药物作用提供了有价值的结构洞察力。4核糖体本身被修饰的耐药性机制对药物化学家来说是一个巨大的挑战。5为了解决这些特殊的机制并促进化学合成，自然产物结构简化(分子编辑)的范例将应用于酮内酯替利红霉素，一种源自旗舰大环内酯类抗生素红霉素A的第三代半合成药物，自2004.7以来一直用于临床，其目的包括(1)应用计算机辅助药物设计工具，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类似物的虚拟文库，以确定最有可能具有生物活性和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)针对药物敏感和耐药细菌菌株进行筛选。这将有助于检验这样一种假设，即复杂大环内酯结构的结构简化将直接解决耐药性问题，而不会损害生物活性。另一轮CADD将用来优化最有前途的候选人。生物检测将衡量这一努力的成功与否。 与公共卫生相关：抗药性细菌菌株数量的增加是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，基于合理的药物设计来制备新药来满足这一需求。