Antibacterial algal natural products that inhibit the bacterial cell division protein FtsZ

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIDDK	VIROL/MICRO-9

Authors

• J Keffer
• A Plaza
• C Bewley

Abstract

Usable antibiotics for drug-resistant microbes are limited, and new antibacterial agents with novel mechanisms of action and biological targets must be developed. An emerging target for antibacterials is the bacterial cell division protein FtsZ, which is the prokaryotic structural homologue of tubulin. FtsZ is conserved among all pathogenic bacteria, and inhibition of its functions will shut down proliferation. Inhibition of FtsZ has potential therapeutic use, but to date, no inhibitors are clinically available. Our lab has recently isolated a novel class of antibacterial agents with potent antibacterial activity and no cytotoxicity towards eukaryotic cell lines. We used spectroscopic techniques to determine the structures, and delineate the structure-activity relationship. Structural similarities with known FtsZ inhibitors led us to test these compounds for their effects on FtsZ. In vitro enzymatic activity assays showed they inhibit GTP hydrolysis in a dose-dependent manner. Furthermore, transmission electron microscopy verified the disruption of GTP-dependent FtsZ filament formation. STD NMR confirmed binding to FtsZ in a competitive manner with an analogue of GTP. Finally, in a tubulin polymerization assay, these compounds had no effect, indicating the interaction with FtsZ is specific. These results are defining the larger picture of FtsZ inhibitor modes of action.

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