RT Journal Article
T1 Synthetic inhibitors of bacterial cell division targeting the GTP-binding site of FtsZ
A1 Ruiz Ávila, Laura
A1 Huecas, Sonia
A1 Artola, Marta
A1 Vergonos, Albert
A1 Ramírez Aportela, Erney
A1 Cercenado, Emilia
A1 Barasoain, Isabel
A1 Vázquez Villa, María Del Henar
A1 Martín-Fontecha Corrales, María Del Mar
A1 Chacón, Pablo
A1 López Rodríguez, María Luz
A1 Andreu, Jose Manuel
AB 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 Bacillus subtilis 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 Staphylococcus aureus and Enterococcus faecalis. 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.
PB ACS Publications
SN 1554-8929
YR 2013
FD 2013-09-01
LK https://hdl.handle.net/20.500.14352/113947
UL https://hdl.handle.net/20.500.14352/113947
LA eng
NO Ruiz-Avila, L. B., Huecas, S., Artola, M., Vergoñós, A., Ramírez-Aportela, E., Cercenado, E., Barasoain, I., Vázquez-Villa, H., Martín-Fontecha, M., Chacón, P., López-Rodríguez, M. L., Andreu, J. M. Synthetic Inhibitors of Bacterial Cell Division Targeting the GTP-Binding Site of FtsZ. ACS Chem. Biol. 2013, 8 (9), 2072-2083
NO Ministerio de Ciencia, Innovación y Universidades
NO Comunidad de Madrid
DS Docta Complutense
RD 7 abr 2025