title: Synthetic inhibitors of bacterial cell division targeting the GTP-binding site of FtsZ.
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 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.
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, Madrid, ‡Dpto. Química Orgánica I, Facultad de Ciencias Químicas, UCM, Madrid, §Instituto de Química-Física Rocasolano, CSIC, Madrid, and ∥Servicio de Microbiología, Hospital General Universitario Gregorio Marañón , Madrid, Spain.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ruiz-Avila
authors.forename: Sonia
authors.initials: S
authors.lastname: Huecas
authors.forename: Marta
authors.initials: M
authors.lastname: Artola
authors.forename: Albert
authors.initials: A
authors.lastname: Vergoñós
authors.forename: Erney
authors.initials: E
authors.lastname: Ramírez-Aportela
authors.forename: Emilia
authors.initials: E
authors.lastname: Cercenado
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.forename: Pablo
authors.initials: P
authors.lastname: Chacón
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: José M
authors.initials: JM
authors.lastname: Andreu
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects; D001419:Bacteria / Q000166:cytology / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D006160:Guanosine Triphosphate / Q000378:metabolism*; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D054852:Small Molecule Libraries; D006160:Guanosine Triphosphate