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

Alyssa McVey, Sean Bartlett, Mahmoud Kajbaf, Annalisa Pellacani, Viviana Gatta, Päivi Tammela, David R. Spring, Martin Welch

Research output: Contribution to journalArticleScientificpeer-review

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.

Original languageEnglish
Article number2490
JournalInternational Journal of Molecular Sciences
Volume21
Issue number7
Number of pages16
ISSN1422-0067
DOIs
Publication statusPublished - 3 Apr 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 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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