Anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents

The histones of Plasmodium falciparum represent a potential new target for anti-malarial compounds. A naturally occurring compound, apicidin, has rece ntly been shown to inhibit the in vitro growth of P. falciparum. Apicidin w as shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. We have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitro growth of a drug sensit ive and resistant strain of P, falciparum. Seven of the tested compounds ha d mu M IC50 values, and trichostatin A, a histone deacetylation inhibitor a nd cytodifferentiating agent, was active at low nM concentrations. One comp ound, suberic acid bisdimethylamide, which selectively arrests tumour cells as opposed to normal mammalian cells, had an in vivo cytostatic effect aga inst the acute murine malaria Plasmodium berghei, and one round of treatmen t with the compound failed to select for resistant mutations. These results suggest a promising role for histone deacetylase inhibitors and cytodiffer entiating agents as antimalarial drug candidates. (C) 2000 Australian Socie ty for Parasitology Inc. Published by Elsevier Science Ltd. All rights rese rved.