Metabolic Engineering of New Streptomyces Sp. from Extreme Environments for Novel Antibiotics and Anticancer Drugs

J.A. Asenjo¹, V. Razmilic^1,2, J.F. Castro^1,2, A. Bull³, M. Goodfellow⁴, M. Jaspars⁵,

M. Bibb² and B.A. Andrews¹

                               ¹Centre for Biochemical Engineering and Biotechnology

                                                             University of Chile

Beauchef 850, Santiago, Chile

²John Innes Centre, Norwich, U.K., ³University of Kent, Canterbury, U.K.,

 ⁴Newcastle University, U.K., ⁵University of Aberdeen, U.K.

juasenjo@ing.uchile.cl

Today there is a tremendous need for new antibiotics and novel cytotoxic compounds against cancer cells to develop efficient alternative treatment to chemotherapy. We have searched for highly active Streptomyces strains in the driest desert in the world, the Atacama desert in northern Chile. We have identified several new strains and found many novel antibiotics and anticancer agents (“Chaxamycins”, “Chaxalactins” and “Atacamycins”) from Streptomyces C34 and C38.

A genome scale model of the metabolism of Streptomyces C34 has been developed from its genome sequence. The model includes 817 reactions including 147 for transport and secondary metabolite biosynthesis such as squalene, pentalenene and desferrioxamine. We have now included reactions for Chaxamycins, Chaxalactins and other polyketides such as the one synthesized by the halogenase cluster. A detailed Metabolic Flux Analysis is presently being carried out in order to optimize synthesis and production of Chaxalactins and Chaxamycins by recognizing appropriate pathways and final useful knock-out sites to increase production of these secondary metabolites.

Alternatively we are identifying the gene cluster in Streptomyces C34 responsible for the biosynthesis of the Chaxamycins and Chaxalactins in order to clone the whole gene cluster in a much more efficient strain of Streptomyces, namely S. coelicolor A3(2) whose heterologous expression of gene clusters from other Streptomyces strains has recently been successfully tested. Our recent results concerning these two alternative strategies for identification and overproduction of these important secondary metabolites will be presented and discussed in this presentation.