The Ovicidal, Larvacidal and Adulticidal Properties of 5,5′-Dimethyl-2,2′-Bipyridyl against Drosophila melanogaster

Abstract

Insecticide resistance has limited the number of available chemical options for insect pest control. Hence there is a need for new chemistries with novel modes of action. Here we investigate the mode of action for an insecticide that has not yet been released for commercial use. The ovicidal, larvacidal and adulticidal effects of 5,5′-dimethyl -2, 2′-dipyridyl (termed Ha44), which is being developed as a treatment for head lice, were evaluated in the Drosophila melanogaster model system. Ha44 demonstrated significant activity against embryos and was capable of arresting development at a number of stages of embryogenesis. The effects of Ha44 on embryos was shown to be reversible following the addition of the metal ions Fe(II) and Fe(III), Cu and Zn. When larvae were exposed to Ha44, lethality was recorded at similar concentrations to those observed for embryos. Using an eYFP reporter system it was shown that Ha44 was able to reduce the levels of both copper and zinc in the digestive tract, confirming the binding of Ha44 to these metals in vivo. Ha44 has further been shown to inhibit a zinc containing metalloproteinase in vitro. Exposure of adult flies to Ha44 resulted in lethality, but at higher concentrations than those observed for embryos and larvae. The median lethal dose in adult flies was shown to be associated with the type of exposure, with an LD-50 of 1.57 mM being recorded following the direct contact of flies with Ha44, while an LD-50 of 12.29 mM was recorded following the ingestion of the compound. The capacity of Ha44 to act on all stages of the life-cycle and potentially via a range of targets suggests that target site resistance is unlikely to evolve.

Ovicidal Efficacy of Abametapir Against Eggs of Human Head and Body Lice (Anoplura: Pediculidae)

“…Previous studies in D. melanogaster indicated that abametapir was capable of arresting a number of stages during embryogenesis. These inhibitory effects, however, were reversible following the addition of certain metal ions (Fe, Cu, and Zn; Van Hiel et al 2012 ). This finding is consistent with the proposed mechanism of action of abametapir, which, as a metal chelating agent, is capable of inhibiting metal-dependent processes, including metalloproteinases, in the louse egg.…”

“…This finding is consistent with the proposed mechanism of action of abametapir, which, as a metal chelating agent, is capable of inhibiting metal-dependent processes, including metalloproteinases, in the louse egg. Indeed, abametapir has previously been shown to inhibit a purified metalloproteinase Meprin A ( Van Hiel et al 2012 ), which has a similar protease domain structure to Zn metalloproteinase, Astacins, which are known to be involved in developmental morphogenesis in a number of species ( Sterchi et al 2008 ). Interestingly, the effects of the additions of Fe, Cu, and Zn to first-instar larvae differed from those additions made to eggs.…”

“…In larvae, the addition of Fe greatly reduced the mortality response to abametapir as it did in eggs. However, the effects of Cu and Zn additions were much less dramatic than in eggs, indicating that the targets in eggs and larvae may differ ( Van Hiel et al 2012 ).…”

“…This key finding provided an opportunity to investigate the role of metalloproteinases as novel ovicidal targets in lice. In an extension of this research, we used the model insect, Drosophila melanogaster , as a means to better understand the ovicidal effects of the compound 5,5′-dimethyl-2,2′-bipyridyl (formerly termed Ha44, now referred to as abametapir; Van Hiel et al 2012 ). Abametapir is a heterocyclic organic molecule that is capable of chelating heavy metal ions, including iron, copper, and zinc, and is therefore able to interact with a range of targets within the insect that require metal co-factors for function, including metalloproteinases.…”

Abametapir for the Treatment of Head Lice: A Drug Review

“…Abametapir, or 5,5′-dimethyl-2,2′bipyridyl, is a heterocyclic organic molecule that inhibits metalloproteinases in part by chelating iron, copper, and zinc cations. 8,9 These metal cofactors are necessary for executing a range of functions in human lice, including the function of various metalloproteinases. 9,10 Metalloproteinases are critical for all stages of head lice ova development, egg hatching, and survival, and inhibition of these metalloproteinases is lethal.…”