Wednesday, August 1, 2007 - 11:00 AM
S147
Biosynthesis of platensimycin and opportunities of engineering novel PTM analogs
Michael J Smanski, Wenli Li, Jianhua Ju, Shuangjun Li, Evelyn Wendt-Pienkowski, and B. Shen. University of Wisconsin-Madison, Madison, WI
Platensimycin (PTM) is the most potent inhibitor reported to date for the FabF subunit of the type II fatty acid synthase and represents the first antibiotic natural product with a new mode of action discovered in over 40 years. Development of PTM into a clinical drug however faces the challenge of poor pharmacokinetics and emergence of resistance. It is therefore important to generate PTM analogs for SAR studies and to understand the mechanism of PTM resistance. As the first step towards these long-term goals, we have initiated a program to study PTM biosynthesis and resistance in the PTM producer Streptomyces platensis. Results on strategies to clone the PTM gene cluster, development of an expedient genetic system for S. platensis, demonstration of the feasibility to manipulate PTM biosynthesis in vivo, and characterization of the PTM biosynthetic machinery featuring novel chemistry will be discussed. These results have now set the stage to study PTM biosynthesis and resistance and to generate PTM analogs by applying combinatorial biosynthesis methods to the PTM biosynthetic machinery.