Ex VivoActivity of Histone Deacetylase Inhibitors against Multidrug-Resistant Clinical Isolates ofPlasmodium falciparumandP. vivax

ABSTRACTHistone acetylation plays an important role in regulating gene transcription and silencing inPlasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potentin vitroactivity against drug-resistant and -sensitive laboratory strains ofP. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specificex vivosusceptibility 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 ofP. falciparum(n= 24) andP. 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 bothP. falciparum(median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) andP. vivax(median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine forP. falciparumand mefloquine forP. vivaxindicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potentex vivoagainstP.vivaxschizont maturation, comparable to that inP. 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 andin vivoefficacy of HDAC inhibitors inPlasmodiumspp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.