Ex vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax

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Title Ex vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax
Author Marfurt, Jutta; Chalfein, Ferryanto; Prayoga, Pak; Wabiser, Frans; Kenangalem, Enny; Piera, Kim A.; Fairlie, David P.; Tjitra, Emiliana; Anstey, Nicholas M.; Andrews, Katherine Thea; Price, Ric N.
Journal Name Antimicrobial Agents and Chemotherapy
Year Published 2011
Place of publication United States
Publisher American Society for Microbiology
Abstract Histone 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1128/AAC.01220-10
Volume 55
Issue Number 3
Page from 961
Page to 966
ISSN 0066-4804
Date Accessioned 2012-02-02; 2012-03-02T04:47:41Z
Research Centre Eskitis Institute for Drug Discovery
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Infectious Agents
URI http://hdl.handle.net/10072/43254
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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