GOALI: E. coli Metabolic Engineering to Produce the Marine Anticancer Agent Lomaiviticin A

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0932612PfeiferIntellectual merit This project originates from a complementary partnership between Tufts University and Wyeth Research. The Wyeth Natural Products Discovery Group is recognized as a leader in industrial natural products-based drug discovery and development and has recently sequenced the gene cluster responsible for a potent anticancer compound called lomaiviticin A. The gene sequence was isolated from the marine bacterium Salinispora pacifica naturally responsible for lomaiviticin A production. Unfortunately, lomaiviticin A production from S. pacifica is time-consuming (7-14 days), inconsistent, and low-yielding (0.5 mg/L). In this project, E. coli will be used as a heterologous host for lomaiviticin A biosynthesis with the logic that E. coli will overcome the current S. pacifica production limitations. Here, the Principal Investigator's (PI's) group at Tufts University will lead efforts to transfer the lomaiviticin A gene cluster to E.coli for subsequent heterologous production. The Tufts team specializes in genetic transfer strategies to facilitate complex natural product production through convenient heterologous hosts. Together, the industrial-academic collaboration is well-suited for the production of this important marine anticancer agent through perhaps the ideal biological host. Broader impactsThe synergistic and complementary academic-industrial partnership between Tufts and Wyeth will promote unique broader impact opportunities. Through Tufts, the project will use research as an educational and outreach mechanism. The research itself crosses numerous disciplines that include: molecular biology, microbiology, chemistry, genetics, and chemical and biological engineering. Students at two educational levels (graduate and undergraduate) will have the opportunity to participate in and learn from this multi-disciplinary approach. In addition, individual research responsibilities have been designed to re-enforce the academic level of the student. The graduate student will oversee and manage the experimental efforts in Aims 1 and 2 while simultaneously guiding undergraduate assistants. Hence, the graduate student will develop as an independent scientist and will also gain mentoring experience as he/she trains younger students. The undergraduate student will learn process culturing and analysis skills that coincide with their chemical and biological engineering curriculum. As part of the outreach initiatives, the undergraduate will be selected from the Tufts NSF-sponsored Computer Science, Engineering, and Mathematics Scholars program that encourages underrepresented groups to pursue science and engineering and for whom the PI serves as an academic advisor. Finally, the students will be able to compare academic and industrial research opportunities and gain first-hand access to both climates through summer internships hosted by Wyeth.