This application for supplemental funding describes experiments in parallel to a broader program aimed at advancing our understanding of prokaryotic cell division as a strategy for developing new antibiotics. In analogy to treating cancer by inhibiting the cytokinesis-modulating protein, tubulin, the homologous bacterial cell division protein, FtsZ, may provide an avenue for curing resistant infections. The proposed experiments in this Supplement will explore the chemistry, biochemistry and microbiology of zantrin Z3, a small molecule inhibitor of FtsZ. Although this compound has been known in the literature for many years, it was originally described in the context of many unselective inhibitors. We were able to demonstrate cross-strain specificity and the absence of unselective inhibition mechanisms common to many inhibitors studied to date. We will use synthetic chemistry, biochemical assays for GTPase inhibition, nuclear magnetic resonance spectroscopy (NMR), and conduct collaborative experiments in X-ray crystallography in order to fully understand how the function of FtsZ is modulated by analogs of this lead compound. Collectively these experiments will advance our understanding of the zantrin Z3 pharmacophore and enable the design of new compounds that will serve as leads in the search for new medicines to treat infection.
The proposed research described in this Supplement will complement the Parent Award by revealing the details of how a small molecule inhibits the activity of a protein (FtsZ) that bacteria need to survive. Preventing it from functioning may be an effective strategy for curing infections that are resistant to antibiotics that target other processes in bacteria. Many bacteria are resistant to most antibiotics that are used today and this research will help in the discovery of new antibiotics to treat infections from these resistant mutants of bacteria.
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