Elucidation of the unusual methylenomycin biosynthetic pathway in Streptomyces coelicolor

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There is an urgent need for improved and new antibiotics due to the increasing emergence of multi-drug resistant pathogens such as vancomycin and methicillin resistant Staphylococcus aureus (VMRSA). One approach to meeting this need is the engineering of natural synthetic (biosynthetic) pathways to antibiotics in producing organisms to generate novel derivatives with potentially superior properties for medical applications. Fundamental knowledge of the genes, enzymes, intermediates and reactions involved in antibiotic biosynthetic pathways is an essential prerequisite for biosynthetic pathway engineering. Methylenomycins belong to an unusual group of antibiotics that have a broad spectrum of activity against Gram-positive and Gram-negative bacteria. Recently the genes required for assembly of the methylenomycins in the microorganism Streptomyces coelicolor have been identified and it has been shown that the methylenomycins are assembled from a unique combination of molecular building blocks. Analysis of the enzymes encoded by the biosynthetic genes indicates that the pathway for methylenomycin biosynthesis is highly novel and does not show similarities to the known pathways for biosynthesis of other antibiotics. This research project aims to investigate the unique methylenomycin biosynthetic pathway by identifying and determining the molecular structure of intermediates on the pathway and examining the role of each of the biosynthetic genes and enzymes. The potential for engineering the pathway to produce novel derivatives of the methylenomycins will also be explored.