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dc.contributor.authorMcVey, Alyssa C
dc.contributor.authorBartlett, Sean
dc.contributor.authorKajbaf, Mahmud
dc.contributor.authorPellacani, Annalisa
dc.contributor.authorGatta, Viviana
dc.contributor.authorTammela, Päivi
dc.contributor.authorSpring, David R
dc.contributor.authorWelch, Martin
dc.date.accessioned2020-05-10T00:23:01Z
dc.date.available2020-05-10T00:23:01Z
dc.date.issued2020-04-03
dc.identifier.issn1422-0067
dc.identifier.otherPMC7177833
dc.identifier.other32260167
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/305163
dc.descriptionFunder: FP7 People: Marie-Curie Actions; Grant(s): 642620
dc.description.abstractPseudomonas 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.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1422-0067
dc.sourcenlmid: 101092791
dc.subjectPseudomonas aeruginosa
dc.subjectenzyme inhibitor
dc.subjectisocitrate lyase
dc.subjectIsothermal Titration Calorimetry
dc.subjectGlyoxylate Shunt
dc.subjectMalate Synthase G
dc.subjectConditionally Essential Target
dc.title2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa.
dc.typeArticle
dc.date.updated2020-05-10T00:23:01Z
prism.issueIdentifier7
prism.publicationNameInternational journal of molecular sciences
prism.volume21
dc.identifier.doi10.17863/CAM.52245
rioxxterms.versionofrecord10.3390/ijms21072490
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidTammela, Päivi [0000-0003-4697-8066]
dc.contributor.orcidSpring, David R [0000-0001-7355-2824]
dc.contributor.orcidWelch, Martin [0000-0003-3646-1733]
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M019411/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/P020291/1)
pubs.funder-project-idAcademy of Finland (277001)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International