Discovery and Characterization of Natural Product Systems-Research Supplement to Promote Diversity

天然产物系统的发现和表征-促进多样性的研究补充

• 批准号: 9905666
• 负责人: DAVID H SHERMAN
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905666
• 关键词: Acinetobacter; Acyl Coenzyme A; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Azithromycin; Bacillus anthracis; Bacteria; Binding; Biological; Biological Assay; Biology; Breathing; Cells; Chemicals; Chimeric Proteins; Clarithromycin; Communities; Complement; Cyclization; Cytochrome P450; Deoxy Sugars; Development; Doctor of Philosophy; Engineering; Erythromycin; Escherichia coli; Exposure to; Funding; Future Generations; Genetic Transcription; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Grant; Growth; Health; Human; Hydroxylation; In Vitro; Ketolides; Laboratories; Latina; Life; Macrolide Antibiotics; Macrolides; Manuscripts; Mediating; Metabolic Biotransformation; Michigan; Minimum Inhibitory Concentration measurement; Mixed Function Oxygenases; Natural Products; Outcomes Research; Pathway interactions; Preparation; Property; Puerto Rican; Research; Ribosomes; Salmonella enterica; Scientist; Specificity; Structure; System; Testing; Therapeutic; Therapeutic Agents; Training Support; Tylosin; Universities; Vancomycin resistant enterococcus; Work; antimicrobial; appendage; design; desosamine; doctoral student; emerging antibiotic resistance; experience; improved; in vitro activity; in vivo evaluation; interest; methicillin resistant Staphylococcus aureus; mutant; next generation; novel; oxidation; parent grant; pathogenic bacteria; pathogenic microbe; picromycin; polyketide synthase; programs; role model; systems research; tool; translation assay

Abstract We are requesting a Research Supplement to Promote Diversity in Health-Related Research to complement the parent grant R35 GM118101 entitled, Discovery and Characterization of Natural Product Systems. The supplement funds are proposed to support Maria Luisa Adrover- Castellano, who is a first year Ph.D. student in the Program of Chemical Biology at the University of Michigan. Maria has the potential and ability to contribute significantly to the overarching goals in the parent grant aimed at understanding the selectivity and specificity employed by modular polyketide synthases (PKSs). As a Latina, Maria is enthusiastic about contributing to the diversity of the university while serving as a role model for future generations of young scientists. Maria's Puerto Rican upbringing exposed her to unique life and cultural experiences, allowing her to offer different points of view. Maria is committed to bringing this diverse perspective to enrich the overall community using her scientific research as an inspiration and powerful tool. We have together developed a plan for her research and growth as a scientist during the Ph.D. tenure. The goals are directed towards the synthesis of unnatural substrates for polyketide synthase (PKS) modules found in the pikromycin biosynthetic pathway. These can be utilized to interrogate different modules, particularly the terminal two PKS monomodules, PikAIII (module 5) and PikAIV (module 6) to produce unnatural macrolactones via biocatalytic transformations. The macrolactones produced through this work can be further converted to their active, antimicrobial counterparts through biotransformations that append a glycosyl group and catalyze regio- and stereospecific oxidations. As a final step, Maria plans to investigate the antibiotic activity of these new macrolides using both an in vitro ribosome inhibition assay, and to determine their relative minimum inhibitory concentrations (MICs) using whole cell bioassays against human pathogenic bacteria. Ultimately, this project relates to the design and development of new macrolide antibiotics, a key objective of the R35 GM118101 grant.

摘要 我们正在申请一份促进健康相关研究多样性的研究补充材料， 补充母基金R35 GM 118101，题为“自然资源的发现和表征”。 产品系统。补充资金拟用于支持Maria Luisa Adrover- 卡斯特拉诺，谁是第一年的博士学位。我是这所大学化学生物学专业的学生 密歇根州。玛丽亚有潜力和能力为总体目标做出重大贡献 在家长资助中，旨在了解模块化所采用的选择性和特异性 聚酮酶（PKS）。作为一名拉丁裔，玛丽亚热衷于为多样性做出贡献。 同时作为未来几代年轻科学家的榜样。玛丽亚的 波多黎各的成长经历使她接触到独特的生活和文化经历，使她能够提供 不同的观点玛丽亚致力于将这种多样化的视角，以丰富整体 社区使用她的科学研究作为灵感和强大的工具。我们在一起 在博士期间，她为自己的研究和科学家的成长制定了一个计划。任职的目标 涉及聚酮化合物合酶（PKS）模块的非天然底物的合成 pikromycin生物合成途径中发现的。这些可以用来询问不同的 模块，特别是终端两个PKS单模块，PikAIII（模块5）和PikAIV（模块 6)以通过生物催化转化产生非天然大环内酯。大环内酯 通过这项工作产生的，可以进一步转化为活性，抗菌对应物 通过附加糖基并催化区域和立体特异性的生物转化， 氧化作为最后一步，玛丽亚计划研究这些新的抗生素活性。 使用体外核糖体抑制测定法测定大环内酯类化合物，并确定它们的相对含量。 使用针对人的全细胞生物测定的最小抑制浓度（MIC） 致病菌最终，该项目涉及新的设计和开发， 大环内酯类抗生素，R35 GM 118101赠款的关键目标。