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dc.contributor.authorMarfurt, Juttaen_US
dc.contributor.authorChalfein, Ferryantoen_US
dc.contributor.authorPrayoga, Paken_US
dc.contributor.authorWabiser, Fransen_US
dc.contributor.authorKenangalem, Ennyen_US
dc.contributor.authorA. Piera, Kimen_US
dc.contributor.authorP. Fairlie, Daviden_US
dc.contributor.authorTjitra, Emilianaen_US
dc.contributor.authorM. Anstey, Nicholasen_US
dc.contributor.authorAndrews, Katherineen_US
dc.contributor.authorN. Price, Ricen_US
dc.description.abstractHistone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum (n = 24) and P. vivax (n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) and P. vivax (median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.en_US
dc.publisherAmerican Society for Microbiologyen_US
dc.publisher.placeUnited Statesen_US
dc.relation.ispartofjournalAntimicrobial agents and Chemotherapyen_US
dc.subject.fieldofresearchInfectious Agentsen_US
dc.titleEx vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivaxen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.hasfulltextNo Full Text

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