2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa

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McVey , A , Bartlett , S , Kajbaf , M , Pellacani , A , Gatta , V , Tammela , P , Spring , D R & Welch , M 2020 , ' 2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa ' , International Journal of Molecular Sciences , vol. 21 , no. 7 , 2490 . https://doi.org/10.3390/ijms21072490

Title: 2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa
Author: McVey, Alyssa; Bartlett, Sean; Kajbaf, Mahmoud; Pellacani, Annalisa; Gatta, Viviana; Tammela, Päivi; Spring, David R.; Welch, Martin
Contributor: University of Helsinki, Division of Pharmaceutical Biosciences
University of Helsinki, Division of Pharmaceutical Biosciences
Date: 2020-04-03
Language: eng
Number of pages: 16
Belongs to series: International Journal of Molecular Sciences
ISSN: 1422-0067
URI: http://hdl.handle.net/10138/317973
Abstract: 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 C-2 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.
Subject: ACIDS
ANTIBIOTICS
ISOCITRATE LYASE
MALATE SYNTHASE
MECHANISM
Pseudomonas aeruginosa
conditionally essential target
enzyme inhibitor
glyoxylate shunt
isocitrate lyase
isothermal titration calorimetry
malate synthase G
317 Pharmacy
116 Chemical sciences
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