Targeting the FtsZ Allosteric Binding Site with a Novel Fluorescence Polarization Screen, Cytological and Structural Approaches for Antibacterial Discovery.
Sonia Huecas, Lidia Araújo-Bazán, Federico M Ruiz, Laura B Ruiz-Ávila, R Fernando Martínez, Andrea Escobar-Peña, Marta Artola, Henar Vázquez-Villa, Mar Martín-Fontecha, Carlos Fernández-Tornero, María L López-Rodríguez, José M Andreu
Author Information
Sonia Huecas: Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Lidia Araújo-Bazán: Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Federico M Ruiz: Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Laura B Ruiz-Ávila: Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
R Fernando Martínez: Dept. Química Orgánica, Facultad de Ciencias Químicas, UCM, Avda. Complutense s/n, 28040 Madrid, Spain. ORCID
Andrea Escobar-Peña: Dept. Química Orgánica, Facultad de Ciencias Químicas, UCM, Avda. Complutense s/n, 28040 Madrid, Spain.
Marta Artola: Dept. Química Orgánica, Facultad de Ciencias Químicas, UCM, Avda. Complutense s/n, 28040 Madrid, Spain. ORCID
Bacterial resistance to antibiotics makes previously manageable infections again disabling and lethal, highlighting the need for new antibacterial strategies. In this regard, inhibition of the bacterial division process by targeting key protein FtsZ has been recognized as an attractive approach for discovering new antibiotics. Binding of small molecules to the cleft between the N-terminal guanosine triphosphate (GTP)-binding and the C-terminal subdomains allosterically impairs the FtsZ function, eventually inhibiting bacterial division. Nonetheless, the lack of appropriate chemical tools to develop a binding screen against this site has hampered the discovery of FtsZ antibacterial inhibitors. Herein, we describe the first competitive binding assay to identify FtsZ allosteric ligands interacting with the interdomain cleft, based on the use of specific high-affinity fluorescent probes. This novel assay, together with phenotypic profiling and X-ray crystallographic insights, enables the identification and characterization of FtsZ inhibitors of bacterial division aiming at the discovery of more effective antibacterials.
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