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Open AccessArticle

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

1
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK
2
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
3
Aptuit LLC, an Evotec Company, 37135 VR Verona, Italy
4
Drug Research Program, Division of Pharmaceutical Biosciences, University of Helsinki, FI-00014 Helsinki, Finland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2490; https://doi.org/10.3390/ijms21072490
Received: 28 February 2020 / Revised: 31 March 2020 / Accepted: 1 April 2020 / Published: 3 April 2020
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. View Full-Text
Keywords: Pseudomonas aeruginosa; glyoxylate shunt; isocitrate lyase; malate synthase G; conditionally essential target; enzyme inhibitor; isothermal titration calorimetry Pseudomonas aeruginosa; glyoxylate shunt; isocitrate lyase; malate synthase G; conditionally essential target; enzyme inhibitor; isothermal titration calorimetry
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McVey, A.C.; Bartlett, S.; Kajbaf, M.; Pellacani, A.; Gatta, V.; Tammela, P.; Spring, D.R.; Welch, M. 2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa. Int. J. Mol. Sci. 2020, 21, 2490.

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