Discovery of Novel Macrolide Antibiotics

新型大环内酯类抗生素的发现

• 批准号: 7566407
• 负责人: RODRIGO B ANDRADE
• 金额: $ 31.99万
• 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/7566407
• 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）：抗生素耐药细菌的快速和不断增加代表了必须解决的严重公共卫生威胁。1经济压力总体上减少了具有活性抗菌研究计划的制药公司的数量，强调2拟议工作的广泛，长期目标是通过发现新型的大花环抗生素来满足这一需求，这些抗生素是通过合理的药物设计直接解决已知耐药机制的。已知大环内酯类抗生素药物作用的机制。3这些药物结合细菌核糖体并防止蛋白质合成。最近，已经解决了与核糖体亚基结合的各种大花环药物（例如红霉素，丝霉素，阿奇霉素）的晶体结构，为这些化合物如何结合（即与核糖核酸残留物接触），为这些化合物如何结合提供了有价值的结构见解（即如何接触） .4核糖体本身修饰的电阻机制代表了对药物化学家的巨大挑战。5为了解决这些特定机制并促进化学合成，自然产品结构简化（分子编辑）的范式将应用于Ketolide远期遗传霉素，将其应用于自2004年以来的第三代半合成药物衍生自2004.7的诊所中使用，在诊所中使用，包括（1）计算机辅助药物设计（CADD）工具的应用，该工具将首先评估所选的麦克罗类模拟库的虚拟库野生型和抗性核糖体亚基都确定最有可能具有生物活性并克服抗性的候选者。在串联中，（2）具有新方法的化学合成将提供对材料的访问，该材料将（3）筛选与药物敏感和耐药的细菌菌株相比。这将有助于检验以下假设：复杂的大花环体系结构的结构简化将直接解决耐药性，而不会损害生物活性。另一轮CADD将有助于优化最有前途的候选人。生物测定将衡量这项努力的成功。 公共卫生相关性：抗生素耐药菌菌株的数量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帮助下根据理性药物设计准备新药来满足这种需求。