title: Effective GTP-replacing FtsZ inhibitors and antibacterial mechanism of action.
abstract: Essential cell division protein FtsZ is considered an attractive target in the search for antibacterials with novel mechanisms of action to overcome the resistance problem. FtsZ undergoes GTP-dependent assembly at midcell to form the Z-ring, a dynamic structure that evolves until final constriction of the cell. Therefore, molecules able to inhibit its activity will eventually disrupt bacterial viability. In this work, we report a new series of small molecules able to replace GTP and to specifically inhibit FtsZ, blocking the bacterial division process. These new synthesized inhibitors interact with the GTP-binding site of FtsZ (Kd = 0.4-0.8 μM), display antibacterial activity against Gram-positive pathogenic bacteria, and show selectivity against tubulin. Biphenyl derivative 28 stands out as a potent FtsZ inhibitor (Kd = 0.5 μM) with high antibacterial activity [MIC (MRSA) = 7 μM]. In-depth analysis of the mechanism of action of compounds 22, 28, 33, and 36 has revealed that they act as effective inhibitors of correct FtsZ assembly, blocking bacterial division and thus leading to filamentous undivided cells. These findings provide a compelling rationale for the development of compounds targeting the GTP-binding site as antibacterial agents and open the door to antibiotics with novel mechanisms of action.
authors.affiliation: †Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Artola
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ruiz-Avila
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Vergoñós
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Huecas
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Araujo-Bazán
authors.affiliation: †Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.affiliation: †Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.affiliation: †Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Turrado
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.|§Instituto de Química-Física Rocasolano, CSIC, E-28006 Madrid, Spain.
authors.forename: Erney
authors.initials: E
authors.lastname: Ramírez-Aportela
authors.affiliation: ∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Hoegl
authors.affiliation: ∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nodwell
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.affiliation: §Instituto de Química-Física Rocasolano, CSIC, E-28006 Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Chacón
authors.affiliation: ∥Center for Integrated Protein Science Munich, Technische Universität München, Department of Chemistry, D-85747 Garching, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.affiliation: ‡Centro de Investigaciones Biológicas, CSIC, E-28040 Madrid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Andreu
authors.affiliation: †Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry*; D007700:Kinetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001713:Biphenyl Compounds; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D009281:Naphthalenes; D006160:Guanosine Triphosphate