Discovery of antimicrobial compounds targeting bacterial type FAD synthetases

Journal of Enzyme Inhibition and Medicinal Chemistry

Isaías Lans¹  Milagros Medina²  María Sebastián²  Ernesto Anoz-Carbonell³  Pilar Cossio⁴  Begoña Gracia⁵  José Antonio Aínsa⁶ 

[1] Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, Medellín, Colombi;Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain;Institute of Biocomputation and Physics of Complex Systems (BIFI-IQFR and CBsC-CSIC Joint Units), Universidad de Zaragoza, Zaragoza, Spain;Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain;Institute of Biocomputation and Physics of Complex Systems (BIFI-IQFR and CBsC-CSIC Joint Units), Universidad de Zaragoza, Zaragoza, Spain;Grupo de Genética de Micobacterias, Departamento de Microbiología, Medicina Preventiva y Salud Pública. Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain;Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt, Germany;Biophysics of Tropical Diseases, Max Planck Tandem Group, University of Antioquia, Medellín, Colombi;Grupo de Genética de Micobacterias, Departamento de Microbiología, Medicina Preventiva y Salud Pública. Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain;CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain;Institute of Biocomputation and Physics of Complex Systems (BIFI-IQFR and CBsC-CSIC Joint Units), Universidad de Zaragoza, Zaragoza, Spain;Grupo de Genética de Micobacterias, Departamento de Microbiología, Medicina Preventiva y Salud Pública. Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain;CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain;

关键词: Bacterial FAD Synthetase;    high-throughput screening;    Streptococcus pneumoniae;    drug discovery;   

DOI  :  10.1080/14756366.2017.1411910

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY