Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina

Bagnall, Neil H., Hines, Barney M., Lucke, Andrew J., Gupta, Praveer K., Reid, Robert C., Fairlie, David P. and Kotze, Andrew C. (2017) Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina. International Journal for Parasitology: Drugs and Drug Resistance, 7 1: 51-60. doi:10.1016/j.ijpddr.2017.01.001


Author Bagnall, Neil H.
Hines, Barney M.
Lucke, Andrew J.
Gupta, Praveer K.
Reid, Robert C.
Fairlie, David P.
Kotze, Andrew C.
Title Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina
Formatted title
Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina
Journal name International Journal for Parasitology: Drugs and Drug Resistance   Check publisher's open access policy
ISSN 2211-3207
Publication date 2017-04-01
Sub-type Article (original research)
DOI 10.1016/j.ijpddr.2017.01.001
Open Access Status DOI
Volume 7
Issue 1
Start page 51
End page 60
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Elsevier
Language eng
Formatted abstract
Histone deacetylase inhibitors (HDACi) are being investigated for the control of various human parasites. Here we investigate their potential as insecticides for the control of a major ecto-parasite of sheep, the Australian sheep blowfly, Lucilia cuprina. We assessed the ability of HDACi from various chemical classes to inhibit the development of blowfly larvae in vitro, and to inhibit HDAC activity in nuclear protein extracts prepared from blowfly eggs. The HDACi prodrug romidepsin, a cyclic depsipeptide that forms a thiolate, was the most potent inhibitor of larval growth, with equivalent or greater potency than three commercial blowfly insecticides. Other HDACi with potent activity were hydroxamic acids (trichostatin, CUDC-907, AR-42), a thioester (KD5170), a disulphide (Psammaplin A), and a cyclic tetrapeptide bearing a ketone (apicidin). On the other hand, no insecticidal activity was observed for certain other hydroxamic acids, fatty acids, and the sesquiterpene lactone parthenolide. The structural diversity of the 31 hydroxamic acids examined here revealed some structural requirements for insecticidal activity; for example, among compounds with flexible linear zinc-binding extensions, greater potency was observed in the presence of branched capping groups that likely make multiple interactions with the blowfly HDAC enzymes. The insecticidal activity correlated with inhibition of HDAC activity in blowfly nuclear protein extracts, indicating that the toxicity was most likely due to inhibition of HDAC enzymes in the blowfly larvae. The inhibitor potencies against blowfly larvae are different from inhibition of human HDACs, suggesting some selectivity for human over blowfly HDACs, and a potential for developing compounds with the inverse selectivity. In summary, these novel findings support blowfly HDAC enzymes as new targets for blowfly control, and point to development of HDAC inhibitors as a promising new class of insecticides.
Keyword Control
Histone deacetylase
Insecticide
Lucilia cuprina
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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