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Overcoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801

Domingo, Riyad; van der Westhuyzen, Renier; Hamann, Anton R.; Mostert, Konrad J.; Barnard, Leanne; Paquet, Tanya; Tjhin, Erick; Saliba, Kevin; van Otterlo, Willem A. L.; Strauss, Erick

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The biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)—the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes—has been validated as a target through extensive genetic knockdown studies in...[Show more]

dc.contributor.authorDomingo, Riyad
dc.contributor.authorvan der Westhuyzen, Renier
dc.contributor.authorHamann, Anton R.
dc.contributor.authorMostert, Konrad J.
dc.contributor.authorBarnard, Leanne
dc.contributor.authorPaquet, Tanya
dc.contributor.authorTjhin, Erick
dc.contributor.authorSaliba, Kevin
dc.contributor.authorvan Otterlo, Willem A. L.
dc.contributor.authorStrauss, Erick
dc.date.accessioned2020-07-20T23:52:20Z
dc.identifier.issn2040-2503
dc.identifier.urihttp://hdl.handle.net/1885/206408
dc.description.abstractThe biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)—the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes—has been validated as a target through extensive genetic knockdown studies in Mycobacterium tuberculosis. Moreover, it has been identified as the molecular target of the fungal natural product CJ-15,801 that shows selective activity against Staphylococcus aureus and the malaria parasite Plasmodium falciparum. As such, CJ-15,801 and 4′-phospho-CJ-15,801 (its metabolically active form) are excellent tool compounds for use in the development of new antimicrobial PPCS inhibitors. Unfortunately, further study and analysis of CJ15,801 is currently being hampered by several unique challenges posed by its synthesis. In this study we describe how these challenges were overcome by using a robust palladium-catalyzed coupling to form the key N-acyl vinylogous carbamate moiety with retention of stereochemistry, and by extensive investigation of protecting groups suited to the labile functional group combinations contained in this molecule. We also demonstrate that using TBAF for deprotection causes undesired off-target effects related to the presence of residual tertiary ammonium salts. Finally, we provide a new method for the chemoenzymatic preparation of 4′-phospho-CJ-15,801 on multi-milligram scale, after showing that chemical synthesis of the molecule is not practical. Taken together, the results of this study advances our pursuit to discover new antimicrobials that specifically target CoA biosynthesis and/or utilization.
dc.description.sponsorshipWe are also grateful to the Canberra branch of the Australian Red Cross Blood Service for providing red blood cells. This work was supported by a CPRR grant (#78988) from the National Research Foundation (NRF) of South Africa and a National Institutes of Health (NIH) award (R01AI136836) to ES. RD received grant-holder and free-standing postdoctoral fellowships from the NRF and postdoctoral study support from the Oppenheimer Memorial Trust, RvdW and LB received NRF Scare Skills doctoral bursaries and KJM an NRF Innovation doctoral bursary. ETT was supported by a Research Training Program scholarship from the Australian Government.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherRoyal Society of Chemistry
dc.rights© The Royal Society of Chemistry 2019
dc.sourceMedChemComm
dc.titleOvercoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume10
dc.date.issued2019
local.identifier.absfor110803 - Medical Parasitology
local.identifier.absfor111501 - Basic Pharmacology
local.identifier.absfor060502 - Infectious Agents
local.identifier.ariespublicationu5786633xPUB1296
local.publisher.urlhttps://www.rsc.org/j
local.type.statusPublished Version
local.contributor.affiliationDomingo, Riyad, Stellenbosch University
local.contributor.affiliationvan der Westhuyzen, Renier, Stellenbosch University
local.contributor.affiliationHamann, Anton R., Stellenbosch University
local.contributor.affiliationMostert, Konrad J., Stellenbosch University
local.contributor.affiliationBarnard, Leanne, Stellenbosch University
local.contributor.affiliationPaquet, Tanya, Stellenbosch University
local.contributor.affiliationTjhin, Erick, College of Science, ANU
local.contributor.affiliationSaliba, Kevin, College of Science, ANU
local.contributor.affiliationvan Otterlo, Willem A. L., Stellenbosch University
local.contributor.affiliationStrauss, Erick, University of Stellenbosch
local.description.embargo2037-12-31
local.bibliographicCitation.issue12
local.bibliographicCitation.startpage2118
local.bibliographicCitation.lastpage2125
local.identifier.doi10.1039/c9md00312f
local.identifier.absseo920109 - Infectious Diseases
dc.date.updated2020-04-12T08:20:16Z
local.identifier.thomsonIDWOS:000502767000008
CollectionsANU Research Publications

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