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

Marfurt, Jutta, Chalfein, Ferryanto, Prayoga, Pak, Wabiser, Frans, Kenangalem, Enny, Piera, Kim A., Fairlie, David P., Tjitra, Emiliana, Anstey, Nicholas M., Andrews, Kathy T. and Price, Rick N. (2011) Ex Vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax. Antimicrobial agents and chemotherapy, 55 3: 961-966. doi:10.1128/AAC.01220-10

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Author Marfurt, Jutta
Chalfein, Ferryanto
Prayoga, Pak
Wabiser, Frans
Kenangalem, Enny
Piera, Kim A.
Fairlie, David P.
Tjitra, Emiliana
Anstey, Nicholas M.
Andrews, Kathy T.
Price, Rick N.
Title Ex Vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax
Journal name Antimicrobial agents and chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1128/AAC.01220-10
Open Access Status File (Publisher version)
Volume 55
Issue 3
Start page 961
End page 966
Total pages 6
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2012
Language eng
Formatted 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 [IC 50s] of 310, 533, and 266 nM) and P. vivax (median IC 50s 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
Keyword Suberoylanilide hydroxamic acid (SAHA)
In-vitro
Antimalarial Activity
Drug-resistance
Chloroquine Resistance
Indonesia
Human Malaria Parasite
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 01 Feb 2012, 08:55:46 EST by Susan Allen on behalf of Institute for Molecular Bioscience