S49: Biosynthetic approaches to novel pactamycin analogs

Pactamycin is a structurally unique and potent antitumor antibiotic isolated from the soil bacterium Streptomyces pactum. It is known to be one of the most complex and densely functionalized aminocyclitol antibiotics. The unusual core aminocyclopentitol structure of pactamycin offers great potential as a scaffold for generating new biologically active compounds. However, efforts to modify the chemical structure of pactamycin using conventional organic synthesis methodology have been difficult due to the complexity of the molecule, calling for an alternative approach to generate structural modifications, e.g., via biosynthetic approaches. The biosynthetic gene cluster of pactamycin has been identified within an 86 kb sequenced region of DNA from S. pactum ATCC 27456. Functional analysis of the genes has been performed by a combination of bioinformatics, enzymatic assays, gene inactivation, as well as chemical and genetic complementation experiments. Using the knowledge obtained from this study, we were able to generate a number of novel analogs of pactamycin, several of which demonstrated potent antibacterial, antitumor, and antimalarial activities.