Latest Malaria Research: Biochemical pathways of multi-drug resistance

Antimicrob Agents Chemother. 2010 Dec 6. [Epub ahead of print]

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

Marfurt J, Chalfein F, Prayoga P, Wabiser F, Kenangalem E, Piera KA, Fairlie DP, Tjitra E, Anstey NM, Andrews KT, Price RN.

Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia; Menzies School of Health Research-National Institute of Health Research and Development Malaria Research Program, Timika, Papua Indonesia; District Ministry of Health, Timika, Papua, Indonesia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia; National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia; Queensland Institute of Medical Research, Herston, Queensland, Australia; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.

Abstract

Histone acetylation plays an important role in regulating gene transcription and silencing in P. 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 anti-malarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors SAHA, 2-ASA-9 and 2-ASA-14 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 IC50 310, 533 and 266 nM) and P. vivax (median IC50 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 anti-malarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium and defining drug interaction with common anti-malarial compounds are warranted to investigate the role of HDAC inhibitors in anti-malarial therapy.
PMID: 21135175 [PubMed - as supplied by publisher]