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

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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.