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2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa.
McVey, Alyssa C; Bartlett, Sean; Kajbaf, Mahmud; Pellacani, Annalisa; Gatta, Viviana; Tammela, Päivi; Spring, David R; Welch, Martin.
Afiliación
  • McVey AC; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
  • Bartlett S; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
  • Kajbaf M; Aptuit LLC, an Evotec Company, 37135 VR Verona, Italy.
  • Pellacani A; Aptuit LLC, an Evotec Company, 37135 VR Verona, Italy.
  • Gatta V; Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, FI-00014 Helsinki, Finland.
  • Tammela P; Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, FI-00014 Helsinki, Finland.
  • Spring DR; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
  • Welch M; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Int J Mol Sci ; 21(7)2020 Apr 03.
Article en En | MEDLINE | ID: mdl-32260167
Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Aminopiridinas / Isocitratoliasa / Malato Sintasa / Antibacterianos Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2020 Tipo del documento: Article Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Aminopiridinas / Isocitratoliasa / Malato Sintasa / Antibacterianos Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2020 Tipo del documento: Article Pais de publicación: Suiza