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<jats:title>ABSTRACT</jats:title><jats:p>Histone acetylation plays an important role in regulating gene transcription and silencing in<jats:italic>Plasmodium falciparum</jats:italic>. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent<jats:italic>in vitro</jats:italic>activity against drug-resistant and -sensitive laboratory strains of<jats:italic>P. falciparum</jats:italic>, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific<jats:italic>ex vivo</jats:italic>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<jats:italic>P. falciparum</jats:italic>(<jats:italic>n</jats:italic>= 24) and<jats:italic>P. vivax</jats:italic>(<jats:italic>n</jats:italic>= 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<jats:italic>P. falciparum</jats:italic>(median 50% inhibitory concentrations [IC<jats:sub>50</jats:sub>s] of 310, 533, and 266 nM) and<jats:italic>P. vivax</jats:italic>(median IC<jats:sub>50</jats:sub>s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for<jats:italic>P. falciparum</jats:italic>and mefloquine for<jats:italic>P. vivax</jats:italic>indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent<jats:italic>ex vivo</jats:italic>against<jats:italic>P</jats:italic>.<jats:italic>vivax</jats:italic>schizont maturation, comparable to that in<jats:italic>P. falciparum</jats:italic>, 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<jats:italic>in vivo</jats:italic>efficacy of HDAC inhibitors in<jats:italic>Plasmodium</jats:italic>spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.</jats:p>

Original publication

DOI

10.1128/aac.01220-10

Type

Journal article

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

03/2011

Volume

55

Pages

961 - 966