Structural studies of target recognition by large natural product antibiotics

大型天然产物抗生素靶标识别的结构研究

• 批准号: 7935142
• 负责人: Patrick J Loll
• 金额: $ 9.33万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935142
• 关键词: Adverse effects; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacitracin; Back; Behavior; Binding; Biological Factors; Cell Wall; Cells; Chemistry; Complement; Complex; Crystallography; Data; Development; Diphosphates; Dissociation; Drug Delivery Systems; Future; Glycopeptide Antibiotics; Glycopeptides; Gramicidin; Group Structure; Hemolysis; Infection; Lead; Ligands; Light; Lipids; Medical History; Membrane; Molecular; Nature; Peptidoglycan; Pharmaceutical Preparations; Play; Prevalence; Process; Public Health; Relative (related person); Research Personnel; Resolution; Roentgen Rays; Role; Structure; Teicoplanin; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Tyrocidine; Vancomycin; Work; antimicrobial; antimicrobial drug; bacterial resistance; base; comparison group; dalbavancin; design; dimer; drug structure; fighting; improved; insight; lipid I; macromolecule; microbial; mimetics; molecular recognition; next generation; novel; novel therapeutics; pathogen; pathogenic bacteria; prenyl; programs; ramoplanin; research study; structural biology

DESCRIPTION (provided by applicant): This proposal focuses on the structural and functional characterization of antimicrobial natural products. The precise molecular details of how these agents fold and how they recognize their targets will be derived from high resolution X-ray crystal structures of drugs and drug:target complexes. Three classes of compounds will be studied. The first class includes vancomycin and related glycopeptide antibiotics. Structural experiments will test hypotheses about the conformational changes accompanying ligand recognition and the role of higher order structural assemblies in peptidoglycan recognition by vancomycin. Structures will also be determined for Group III (teicoplanin-like) antibiotics, including the newly introduced therapeutic agent dalbavancin, allowing for a comparison of Group I (vancomycin-like) and Group III antibiotics, and illuminating how ligand recognition and oligomerization behavior differ between the two groups. Novel glycopeptide compounds have been designed based upon existing structural data, and will be synthesized and characterized. The second class of bacteriocidal natural products to be studied are molecules that recognize polyprenyl pyrophosphate-containing ligands on bacterial cells, such as the Lipid II intermediate in peptidoglycan biosynthesis. Crystallographic studies will be used to reveal the determinants of molecular recognition for these different agents, in an effort to establish their mechanisms of action and informing the future design of related therapeutic agents. The specific molecules under study include ramoplanin, enduracidin, and bacitracin. The third class of antibiotics comprises cyclic decapeptides that permeabilize bacterial membranes. While these are effective antimicrobials, they can also be hemolytic; therefore crystallography will be used to study the structures of an array of compounds with differing bacteriocidal and hemolytic activities. Comparison of these will identify the structural determinants that control the desired antibacterial activity and the unwanted side effects, and thus aid in the development of improved agents. Relevance to public health: The prevalence of resistant bacterial pathogens is rendering current antibiotics ineffective, and making it essential that new drugs be developed to fight infection. This project will provide essential information about naturally occurring antimicrobial compounds. This information will facilitate the rational development of these natural compounds into next generation therapeutic agents.

描述（由申请人提供）：本提案侧重于抗菌天然产物的结构和功能表征。这些药物如何折叠以及它们如何识别靶标的精确分子细节将来自药物和药物：靶标复合物的高分辨率X射线晶体结构。将研究三类化合物。第一类包括万古霉素和相关的糖肽类抗生素。结构实验将检验有关配体识别伴随的构象变化和更高级结构组装体在万古霉素肽聚糖识别中的作用的假设。还将确定III组（替考拉宁样）抗生素的结构，包括新引入的治疗剂达巴霉素，从而比较I组（万古霉素样）和III组抗生素，并阐明两组之间的配体识别和寡聚化行为如何不同。新的糖肽化合物已被设计基于现有的结构数据，并将被合成和表征。待研究的第二类杀菌天然产物是识别细菌细胞上含有焦磷酸聚异戊二烯酯的配体的分子，例如肽聚糖生物合成中的脂质II中间体。晶体学研究将用于揭示这些不同药物的分子识别决定因素，以建立其作用机制并为相关治疗药物的未来设计提供信息。正在研究的特定分子包括雷莫拉宁、雷帕霉素和杆菌肽。第三类抗生素包括使细菌膜透化的环状十肽。虽然这些是有效的抗菌剂，但它们也可能是溶血性的;因此，晶体学将用于研究具有不同杀菌和溶血活性的一系列化合物的结构。这些比较将确定控制所需抗菌活性和不需要的副作用的结构决定因素，从而有助于开发改进的药物。 与公共卫生的相关性：耐药细菌病原体的流行使目前的抗生素无效，并使开发新药以对抗感染变得至关重要。该项目将提供有关天然存在的抗菌化合物的基本信息。这些信息将促进这些天然化合物合理开发为下一代治疗药物。