The goal of this proposal is to demonstrate that certain antimicrobial natural products derive their biological activity from inhibition of ftsZ, the bacterial analog of mammalian tubulin that is required for bacterial cell division. FtsZ is an exciting new target for developing new methods of combating bacterial infections that are currently resistant to other forms of therapy. To date, very few small molecules have been shown to inhibit ftsZ, and the few that do so are toxic to mammalian cells. Research at the ICCB has revealed several new small molecules that inhibit ftsZ, 1 of which shares a common core structure with a series of known antibiotic natural products. These natural products are derived from plant extracts that are currently used for traditional medicine, so it is likely that there mammalian toxicity is quite low. We will synthesize these natural products so that their biological mode of action can be discerned. In the process, we will develop new and highly efficient chemical reactions that allow rapid and flexible assembly of the core structures, and use these synthetic techniques in a diversity-oriented approach to a variety of structural analogs. If successful, this proposal will demonstrate that plant-derived compounds, as well as synthetic analogs thereof, will inhibit ftsZ and offer some hope of discovering compounds that exploit this unique mode of activity for therapeutic value. ? ?
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| Urgaonkar, Sameer; Shaw, Jared T (2007) Synthesis of kaempferitrin. J Org Chem 72:4582-5 |
| Mukherjee, Shubhasish; Robinson, Carolyn A; Howe, Andrew G et al. (2007) N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli. Bioorg Med Chem Lett 17:6651-5 |
| Urgaonkar, Sameer; La Pierre, Henry S; Meir, Israel et al. (2005) Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2' ''-hydroxy-5' '-benzylisouvarinol-B. Org Lett 7:5609-12 |
