Hygromycin A: Activity, Biosynthesis, Export, Resistance and Regulation

潮霉素 A：活性、生物合成、输出、耐药性和监管

• 批准号: 8023746
• 负责人: KEVIN A REYNOLDS
• 金额: $ 30.46万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8023746
• 关键词: Actinobacteria class; Address; Aminoglycosides; Anabolism; Antibiotic Resistance; Antibiotics; Architecture; Azithromycin; Bacteria; Bacterial Infections; Binding; Biochemical; Biological; Biological Factors; Cells; Chemicals; Chromosomes; Clinical; Complex; Development; Enzymatic Biochemistry; Enzymes; Gene Cluster; Gene Expression; Genes; Genetic; Gram-Negative Bacteria; Infection; Lead; Linezolid; Macrolides; Modification; Molecular; Multi-Drug Resistance; Organism; Oxazolidinones; Pathway interactions; Process; Protein Biosynthesis; Proteins; Regulation; Relative (related person); Resistance; Resistance Process; Resistance development; Ribonucleoproteins; Ribosomal Interaction; Ribosomes; Role; Shunt Device; Soil; Source; Staging; Streptomyces; Structure; Tetracyclines; Work; antibiotic efflux; bacterial resistance; base; biosynthetic product; drug development; drug resistant bacteria; fascinate; hygromycin A; insight; interdisciplinary approach; interest; microbial; microorganism; mutant; novel; repository; resistance mechanism; telithromycin; uptake

DESCRIPTION (provided by applicant): Many clinically important classes of antibiotics, including macrolides (azithromycin, telithromycin), tetracyclines, aminoglycosides (gentamycin), and more recently oxazolidinones (linezolid) target the bacterial ribosome, which is essential for intracellular protein synthesis. Use of these and other antibiotics against pathogenic microorganisms inevitably leads to development of bacterial resistance, an increasing problem within the clinical setting. There is thus a continued need to develop new antibiotics, effective against multi-drug resistant bacteria, and for approaches which can retard the inevitable development of resistance to these. The ribosome represents one of the richest and most effective targets for development of new antibiotics. Such drug development efforts can build upon a molecular level understanding of the ribosomal interactions with chemically distinct architectures, structural requirements for other aspects of biologically activity (including cellular uptake) and likely mechanisms for development of resistance. Hygromycin A (HygA), an antibiotic isolated from Streptomyces hygroscopicus and is active against both Gram-positive and Gram-negative bacteria and a mechanism of action which involves a distinct but enigmatic binding to the ribosome. HygA also has a chemical architecture which differs significantly from other antibiotics which target the ribosome. For these reasons HygA is of interest for potential development into new class of clinically-useful antibiotics. The long term project objective is to build a comprehensive understanding of hygromycin A (HygA) activity, biosynthesis, export, resistance and regulation (ABERR). This project period has 5 specific aims which will be pursed using a multi-interdisciplinary and collaborative approach with genetic, biochemical and structural studies. Aim 1. Obtain a detailed understanding of the enzymology of key and novel steps in the HygA biosynthetic process. Aim 2. Elucidate how HygA, biosynthetic pathway intermediates and shunt products, bind to ribosomes. Aim 3. Determine mechanisms by which the final product HygA is excreted from the cell. Aim 4. Evaluate the relative roles of covalent modification of both the antibiotic and the S. hygroscopicus ribosome in conferring resistance to HygA and related biosynthetic products. Aim 5. Determine how HygA ABERR processes are regulated, and to what extent are they coordinated. PUBLIC HEALTH RELEVANCE: There is continued need for new antibiotics effective against multi-drug resistant bacteria, and for approaches which can retard the inevitable development of resistance to these. Actinomycetes are soil bacteria and serve both as a source for the majority of antibiotics used clinically to treat bacterial infections and a repository for resistance mechanisms to these. This study will evaluate biological activity and resistance mechanisms associated with the natural product hygromycin A and related compounds and may ultimately lead to new therapies for treatment of bacterial infections.

描述（由申请人提供）：许多临床上重要的抗生素类别，包括大环内酯类（阿奇霉素、泰利霉素）、四环素类、氨基糖苷类（庆大霉素）和最近的恶唑烷酮类（利奈唑胺）以细菌核糖体为目标，而细菌核糖体对于细胞内蛋白质合成至关重要。使用这些抗生素和其他抗生素来对抗病原微生物不可避免地会导致细菌耐药性的产生，这是临床环境中日益严重的问题。因此，持续需要开发有效对抗多重耐药细菌的新抗生素，以及能够延缓对这些细菌不可避免的耐药性发展的方法。核糖体是开发新抗生素最丰富、最有效的靶标之一。此类药物开发工作可以建立在对核糖体与化学上不同结构的相互作用、生物活性其他方面（包括细胞摄取）的结构要求以及产生耐药性的可能机制的分子水平理解的基础上。 潮霉素 A (HygA) 是一种从吸水链霉菌中分离出来的抗生素，对革兰氏阳性和革兰氏阴性细菌都有活性，其作用机制涉及与核糖体的独特但神秘的结合。 HygA 还具有与其他靶向核糖体的抗生素显着不同的化学结构。由于这些原因，HygA 有望开发成新型临床有用抗生素。 项目的长期目标是全面了解潮霉素 A (HygA) 的活性、生物合成、输出、耐药性和调节 (ABERR)。该项目期间有 5 个具体目标，将通过遗传、生化和结构研究的多跨学科和协作方法来实现。目标 1. 详细了解 HygA 生物合成过程中关键和新步骤的酶学。目标 2. 阐明 HygA、生物合成途径中间体和分流产物如何与核糖体结合。目标 3. 确定最终产物 HygA 从细胞中排出的机制。目标 4. 评估抗生素和吸水链球菌核糖体的共价修饰在赋予 HygA 和相关生物合成产品抗性方面的相对作用。目标 5. 确定 HygA ABERR 过程的监管方式以及它们的协调程度。 公共卫生相关性：仍然需要有效对抗多重耐药细菌的新型抗生素，以及能够延缓耐药性不可避免发展的方法。放线菌是土壤细菌，既是临床上用于治疗细菌感染的大多数抗生素的来源，又是这些抗生素的耐药机制的储存库。这项研究将评估与天然产物潮霉素 A 和相关化合物相关的生物活性和耐药机制，并可能最终带来治疗细菌感染的新疗法。