Comparison of Small Molecule
Inhibitors of the Bacterial
Cell Division Protein FtsZ and Identification of a Reliable Cross-Species
Inhibitor
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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