Histone deacetylase enzymes as drug targets for the control of the sheep blowfly, Lucilia cuprina.
The Australian sheep blowfly, Lucilia cuprina, is an ecto-parasite that causes significant economic losses in the sheep industry. Emerging resistance to insecticides used to protect sheep from this parasite is driving the search for new drugs that act via different mechanisms. Inhibitors of histone deacetylases (HDACs), enzymes essential for regulating eukaryotic gene transcription, are prospective new insecticides based on their capacity to kill human parasites. The blowfly genome was found here to contain five HDAC genes corresponding to human HDACs 1, 3, 4, 6 and 11. The catalytic domains of blowfly HDACs 1 and 3 have high sequence identity with corresponding human and other Dipteran insect HDACs (Musca domestica and Drosophila melanogaster). On the other hand, HDACs 4, 6 and 11 from the blowfly and the other Dipteran species showed up to 53% difference in catalytic domain amino acids from corresponding human sequences, suggesting the possibility of developing HDAC inhibitors specific for insects as desired for a commercial insecticide. Differences in transcription patterns for different blowfly HDACs through the life cycle, and between the sexes of adult flies, suggest different functions in regulating gene transcription within this organism and possibly different vulnerabilities. Data that supports HDACs as possible new insecticide targets is the finding that trichostatin A and suberoylanilide hydroxamic acid retarded growth of early instar blowfly larvae in vitro, and reduced the pupation rate. Trichostatin A was 8-fold less potent than the commercial insecticide cyromazine in inhibiting larval growth. Our results support further development of inhibitors of blowfly HDACs with selectivity over human and other mammalian HDACs as a new class of prospective insecticides for sheep blowfly.
CSIRO Agriculture, St. Lucia, Queensland 4067, Australia. Electronic address: Andrew.kotze@csiro.au.
Andrew C
AC
Kotze
CSIRO Agriculture, St. Lucia, Queensland 4067, Australia.
Barney M
BM
Hines
CSIRO Agriculture, St. Lucia, Queensland 4067, Australia.
Neil H
NH
Bagnall
Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia.
Clare A
CA
Anstead
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Praveer
P
Gupta
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
Robert C
RC
Reid
CSIRO Agriculture, St. Lucia, Queensland 4067, Australia.
Angela P
AP
Ruffell
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
David P
DP
Fairlie
D000818:Animals; D004175:Diptera / Q000187:drug effects* / Q000201:enzymology*; D016678:Genome; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008018:Life Cycle Stages; D010802:Phylogeny; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077337:Vorinostat; D006655:Histone Deacetylases
Histone deacetylase; Insecticide; Lucilia cuprina; Trichostatin