Monday, July 30, 2007
P66

Towards new bleomycin group antibiotics: Investigations on the biosynthetic pathways of bleomycin, zorbamycin, and tallysomycin in wild-type and recombinant strains of the respective producer organisms

Ute Galm, Jane M. Coughlin, Meifeng Tao, Liyan Wang, Evelyn Wendt-Pienkowski, Guodong Zhang, and Ben Shen. University of Wisconsin-Madison, 777 Highland Ave, Madison, WI 53705

The anticancer drug bleomycin (BLM) and the related compounds zorbamycin (ZBM) and tallysomycin (TLM) are prominent members of glycosylated hybrid peptide-polyketide antibiotics.  Blenoxane®, the clinically used product, contains BLM A2 and B2 as the principle constituents.  Analysis of the BLM and, more recently, TLM and ZBM biosynthetic gene clusters provided new insights into the biosynthetic machinery and resistance mechanisms shared by these compounds, yet revealed significant differences.  In-depth investigations, however, have so far been hampered by low productivity of the respective Streptomyces strains and the lack of an efficient genetic system.  Hence, we set out to develop tools for in vivo engineering of the producer strains as important prerequisites for combinatorial biosynthetic approaches.  We now present successful genetic manipulations of the BLM, ZBM, and TLM producing organisms including the establishment of cluster boundaries, and we shed light on selected enzymatic reactions within the complex biosynthetic pathways of these compounds.  The findings from our studies implicate new strategies to rationally construct hybrid nonribosomal peptide synthetase - polyketide synthase systems, and will eventually lead to novel BLM analogs with improved therapeutic efficacy as future anticancer drugs.

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