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  Discovery of antimicrobial compounds targeting bacterial type FAD synthetases

Sebastián, M., Anoz-Carbonell, E., Gracia, B., Cossio, P., Aínsa, J. A., Lans, I., et al. (2018). Discovery of antimicrobial compounds targeting bacterial type FAD synthetases. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 241-254. doi:10.1080/14756366.2017.1411910.

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 Creators:
Sebastián, María1, 2, Author
Anoz-Carbonell, Ernsesto1, 2, 3, Author
Gracia, Begoña3, 4, Author
Cossio, Pilar5, 6, Author           
Aínsa, José Antonio 2, 3, 4, Author
Lans, Isaías 6, Author
Medina, Milagros1, 2, Author
Affiliations:
1Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain, ou_persistent22              
2Institute of Biocomputation and Physics of Complex Systems (BIFI-IQFR and CBsC-CSIC Joint Units), Universidad de Zaragoza, Zaragoza, Spain, ou_persistent22              
3Grupo de Genética de Micobacterias, Departamento de Microbiología, Medicina Preventiva y Salud Pública. Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain, ou_persistent22              
4CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain, ou_persistent22              
5Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
6Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, Medellín, Colombia, ou_persistent22              

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Free keywords: Bacterial FAD Synthetase; high-throughput screening; Streptococcus pneumoniae; drug discovery
 Abstract: The increase of bacterial strains resistant to most of the available antibiotics shows a need to explore novel antibacterial targets to discover antimicrobial drugs. Bifunctional bacterial FAD synthetases (FADSs) synthesise the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These cofactors act in vital processes as part of flavoproteins, making FADS an essential enzyme. Bacterial FADSs are potential antibacterial targets because of differences to mammalian enzymes, particularly at the FAD producing site. We have optimised an activity-based high throughput screening assay targeting Corynebacterium ammoniagenes FADS (CaFADS) that identifies inhibitors of its different activities. We selected the three best high-performing inhibitors of the FMN:adenylyltransferase activity (FMNAT) and studied their inhibition mechanisms and binding properties. The specificity of the CaFADS hits was evaluated by studying also their effect on the Streptococcus pneumoniae FADS activities, envisaging differences that can be used to discover species-specific antibacterial drugs. The antimicrobial effect of these compounds was also evaluated on C. ammoniagenes, S. pneumoniae, and Mycobacterium tuberculosis cultures, finding hits with favourable antimicrobial properties

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Language(s): eng - English
 Dates: 2017-10-172017-11-282017-12-192018-01
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1080/14756366.2017.1411910
 Degree: -

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Title: Journal of Enzyme Inhibition and Medicinal Chemistry
  Other : J. Enzym. Inhib. Med. Chem.
Source Genre: Journal
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Publ. Info: Basingstoke, UK : Taylor & Francis
Pages: - Volume / Issue: 33 (1) Sequence Number: - Start / End Page: 241 - 254 Identifier: ISSN: 1475-6366
CoNE: https://pure.mpg.de/cone/journals/resource/954925626348