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dc.contributor.authorAndrews, Kathy
dc.contributor.authorFisher, Gillian
dc.contributor.authorRiches, Andrews
dc.contributor.authorHutt, Oliver
dc.contributor.authorJarvis, Karen
dc.contributor.authorWilson, Tony
dc.contributor.authorvon Itzstein, Mark
dc.contributor.authorChopra, Pradeep
dc.contributor.authorAntonova-Koch, Yevgeniya
dc.contributor.authorMeister, Stephan
dc.contributor.authorWinzeler, Elizabeth
dc.contributor.authorClarke, Mary
dc.contributor.authorFidock, David
dc.contributor.authorBurrows, Jeremy
dc.contributor.authorRyan, John
dc.contributor.authorSkinner-Adams, Tina
dc.date.accessioned2020-03-26T02:14:48Z
dc.date.available2020-03-26T02:14:48Z
dc.date.issued2019
dc.identifier.issn0002-9637
dc.identifier.doi10.4269/ajtmh.abstract2019
dc.identifier.urihttp://hdl.handle.net/10072/392642
dc.description.abstractMalarone® is a combination of atovaquone and proguanil that is used for malaria prophylaxis and treatment. Atovaquone has potent antiplasmodium activity as a cytochrome bc1-inhibitor while dogma is that proguanil does not have potent intrinsic activity. Proguanil can, however, potentiate atovaquone activity and its cyclization-metabolite (cycloguanil) is a dihydrofolate reductase inhibitor with potent activity. We have recently found that proguanil, and an analogue that cannot convert to cycloguanil (tBuPG), have potent slow-acting activity in vitro against asexual P. falciparum parasites. This activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast DHODH-expressing parasites, proguanil and tBuPG slow action activity remains, however bc1- inhibitor activity switches from fast to slow-acting. Proguanil and tBuPG both act synergistically with bc1-inhibitors, while cycloguanil antagonizes activity. Overall, our data suggest that proguanil has potent slow-acting activity against asexual-stage P. falciparum, that bc1 is essential to parasite survival independent of DHODH-activity and that Malarone® may act as a triple-drug combination (including antagonistic partners). These findings raise the possibility that a cyclization-blocked proguanil may be a better in vivo combination partner for antimalarial bc1-inhibitors.
dc.languageEnglish
dc.publisherAmerican Society of Tropical Medicine and Hygiene
dc.relation.ispartofconferencename68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH)
dc.relation.ispartofconferencetitleAMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
dc.relation.ispartofdatefrom2019-11-20
dc.relation.ispartofdateto2019-11-24
dc.relation.ispartoflocationNational Harbor, MD
dc.relation.ispartofpagefrom270
dc.relation.ispartofpageto270
dc.relation.ispartofvolume101
dc.subject.fieldofresearchMedical Microbiology
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode1108
dc.subject.fieldofresearchcode11
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsPublic, Environmental & Occupational Health
dc.subject.keywordsTropical Medicine
dc.titleNew insights into the mode of action of the antimalarial drug proguanil
dc.typeConference output
dc.type.descriptionE3 - Conferences (Extract Paper)
dcterms.bibliographicCitationAndrews, K; Fisher, G; Riches, A; Hutt, O; Jarvis, K; Wilson, T; von Itzstein, M; Chopra, P; Antonova-Koch, Y; Meister, S; Winzeler, E; Clarke, M; Fidock, D; Burrows, J; Ryan, J; Skinner-Adams, T, New insights into the mode of action of the antimalarial drug proguanil, American Journal of Tropical Medicine and Hygiene, 2019, 101, pp. 270-270
dc.date.updated2020-03-26T01:31:12Z
dc.description.versionPublished
gro.rights.copyright© 2019 American Society of Tropical Medicine and Hygiene. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorvon Itzstein, Mark
gro.griffith.authorSkinner-Adams, Tina
gro.griffith.authorFisher, Gill M.
gro.griffith.authorClarke, Mary
gro.griffith.authorChopra, Pradeep
gro.griffith.authorAndrews, Katherine T.


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