Comparison of small molecule inhibitors of the bacterial cell division protein ftsz and identification of a reliable cross-species inhibitor

David E. Anderson, Michelle B. Kim, Jared T. Moore, Terrence E. O'Brien, Nohemy A. Sorto, Charles I. Grove, Laura L. Lackner, James B. Ames, Jared T. Shaw

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

FtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin's function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross-comparison of reported FtsZ inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two side chains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively, these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.

Original languageEnglish (US)
Pages (from-to)1918-1928
Number of pages11
JournalACS Chemical Biology
Volume7
Issue number11
DOIs
StatePublished - Nov 16 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Anderson, D. E., Kim, M. B., Moore, J. T., O'Brien, T. E., Sorto, N. A., Grove, C. I., Lackner, L. L., Ames, J. B., & Shaw, J. T. (2012). Comparison of small molecule inhibitors of the bacterial cell division protein ftsz and identification of a reliable cross-species inhibitor. ACS Chemical Biology, 7(11), 1918-1928. https://doi.org/10.1021/cb300340j