Targeting the FtsZ Allosteric Binding Site with a Novel Fluorescence Polarization Screen, Cytological and Structural Approaches for Antibacterial Discovery
| Autor: | Federico M. Ruiz, Andrea Escobar-Peña, María L. López-Rodríguez, José Manuel Andreu, Mar Martín-Fontecha, Sonia Huecas, Marta Artola, Henar Vázquez-Villa, Laura B. Ruiz-Avila, Lidia Araújo-Bazán, R Fernando Martínez, Carlos Fernández-Tornero |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Huecas, Sonia [0000-0002-6419-441X], Araújo-Bazán, Lidia [0000-0002-8750-7706], Ruiz, Federico M. [0000-0002-0385-7777], Martínez, R. Fernando [0000-0002-3278-6074], Artola, M. [0000-0002-3051-3902], Vazquez-Villa, Henar [0000-0001-7911-3160], Martin-Fontecha, M. [0000-0002-4848-0109], Fernández-Tornero, Carlos [0000-0001-5097-731X], Lopez-Rodriguez, M.L. [0000-0001-8607-1085], Andreu, José Manuel [0000-0001-8064-6933], Huecas, Sonia, Araújo-Bazán, Lidia, Ruiz, Federico M., Martínez, R. Fernando, Artola, M., Vazquez-Villa, Henar, Martin-Fontecha, M., Fernández-Tornero, Carlos, Lopez-Rodriguez, M.L., Andreu, José Manuel |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Staphylococcus aureus
GTP' Pyridines Allosteric regulation Fluorescence Polarization Computational biology Microbial Sensitivity Tests Guanosine triphosphate Crystallography X-Ray Ligands 01 natural sciences Fluorescence Article Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Bacterial Proteins Drug Discovery Magnetic properties FtsZ 030304 developmental biology Fluorescent Dyes 0303 health sciences biology Chemistry Inhibitors Química orgánica Phenotype Small molecule Screening assays 0104 chemical sciences Anti-Bacterial Agents 010404 medicinal & biomolecular chemistry Cytoskeletal Proteins Benzamides biology.protein Molecular Medicine Probes Fluorescence anisotropy Function (biology) Allosteric Site Bacillus subtilis Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry E-Prints Complutense. Archivo Institucional de la UCM instname Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Digital.CSIC. Repositorio Institucional del CSIC |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 51 p.-6 fig.-1 tab.-4 schem.-1 graph. abst. 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. Thiswork was supported by grants BFU 2014-51823-R (J.M.A.),SAF2016-78792-R, PID2019-106279RB-I00 (M.L.L.-R.), BFU2017-87387-P (C.F.-T.), and predoctoral FPU fellowshipsfrom MECD (A.E.-P. and M.A.). |
| Databáze: | OpenAIRE |
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