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

摘要 我们正在请求一份研究补充资料，以促进与健康相关的研究的多样性，以 补充母基金R35 GM118101，题为：发现和表征自然 产品系统。建议的补充资金是为了支持玛丽亚·路易莎·阿德罗弗- 卡斯特拉诺是该大学化学生物学专业的一年级博士生 来自密歇根州。玛丽亚有潜力和能力为总体目标做出重大贡献。 在父级拨款中，旨在了解模块化所采用的选择性和专一性 聚酮合成酶(PKS)。作为一名拉丁裔，玛丽亚热衷于为多样性做出贡献 他是这所大学的杰出代表，同时也是未来几代青年科学家的榜样。玛丽亚的 波多黎各的成长使她接触到独特的生活和文化体验，使她能够提供 不同的观点。Maria致力于将这种不同的视角带到丰富的整体 她把她的科学研究作为一种灵感和有力的工具。我们在一起 在博士任期内，作为一名科学家，她制定了一项研究和成长计划。目标 针对聚酮合成酶(PKS)模块的非天然底物的合成 在吡克罗霉素的生物合成途径中发现。这些可以用来询问不同的 模块，特别是终端两个PKS单模，PikAIII(模块5)和PikAIV(模块 6)通过生物催化转化生成非天然大内酯。大内酯类药物 通过这项工作产生的产物可以进一步转化为活性的、抗菌的对应物 通过添加糖基并催化区域和立体特异性的生物转化 氧化作用。作为最后一步，玛丽亚计划调查这些新的抗生素活性 用体外核糖体抑制法测定大环内酯类化合物的相对含量 用全细胞生物测定法测定人的最低抑菌浓度 病原菌。最终，这个项目涉及到新的 大环内酯类抗生素，R35 GM118101赠款的关键目标。

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.