Targeting the FtsZ Allosteric Binding Site with a Novel Fluorescence Polarization Screen, Cytological and Structural Approaches for Antibacterial Discovery

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...

Descripción completa

Detalles Bibliográficos
Autores: Huecas, Sonia, Araujo Bazán, Lidia, Ruiz, Federico, Ruiz Ávila, Laura, Martínez, R. Fernando, Escobar Peña, Ana Andrea, Artola, Marta, Vázquez Villa, María Del Henar, Martín-Fontecha Corrales, María Del Mar, Fernández Tornero, Carlos, López Rodríguez, María Luz, Andreu, José M.
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/8590
Acceso en línea:https://hdl.handle.net/20.500.14352/8590
Access Level:acceso abierto
Palabra clave:543.426
616.993.192.6
615.28
547
Fluorescence
Magnetic properties
Inhibitors
Screening assays
Probes
Química orgánica (Química)
Bioquímica (Química)
2306 Química Orgánica
2302 Bioquímica
3108.01 Bacterias
Descripción
Sumario: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.

Similares en LA Referencia