Synthetic Inhibitors of Bacterial Cell Division Targeting
the GTP-Binding Site of FtsZ
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Abstract
Cell division protein FtsZ is the
organizer of the cytokinetic
Z-ring in most bacteria and a target for new antibiotics. FtsZ assembles
with GTP into filaments that hydrolyze the nucleotide at the association
interface between monomers and then disassemble. We have replaced
FtsZ’s GTP with non-nucleotide synthetic inhibitors of bacterial
division. We searched for these small molecules among compounds from
the literature, from virtual screening (VS), and from our in-house
synthetic library (UCM), employing a fluorescence anisotropy primary
assay. From these screens we have identified the polyhydroxy aromatic
compound UCM05 and its simplified analogue UCM44 that specifically
bind to <i>Bacillus subtilis</i> FtsZ monomers with micromolar
affinities and perturb normal assembly, as examined with light scattering,
polymer sedimentation, and negative stain electron microscopy. On
the other hand, these ligands induce the cooperative assembly of nucleotide-devoid
archaeal FtsZ into distinct well-ordered polymers, different from
GTP-induced filaments. These FtsZ inhibitors impair localization of
FtsZ into the Z-ring and inhibit bacterial cell division. The chlorinated
analogue UCM53 inhibits the growth of clinical isolates of antibiotic-resistant <i>Staphylococcus aureus</i> and <i>Enterococcus faecalis</i>. We suggest that these interfacial inhibitors recapitulate binding
and some assembly-inducing effects of GTP but impair the correct structural
dynamics of FtsZ filaments and thus inhibit bacterial division, possibly
by binding to a small fraction of the FtsZ molecules in a bacterial
cell, which opens a new approach to FtsZ-based antibacterial drug
discovery