Insect Control: Biological and Synthetic Agents - Index of

For the spinosyns and spinosoids, HOMO appears
to be directly influenced by substitution on the
forosamine nitrogen (Sparks et al., 2000b) suggesting
that the primary drivers for activity are CLogP and
Mopac dipole moment. In turn, Mopac dipole
moment appears rather well correlated with the
substitution pattern on the rhamnose moiety, and
secondarily by substitution on the forosamine nitrogen
(Sparks et al., 2001). As implied by the above
equations, the most active spinosyns and spinosoids
tend to have smaller values for Mopac dipole moment
and larger values (up to a point) for CLogP
(Sparks et al., 2001). Thus, these relationships provide
a useful basis for understanding spinosyn and
spinosoid activity not only against lepidopteran insect
pests but also for other pest insects, including
aphids and leafhoppers (Dintenfass et al., 2001).
CAMD and QSAR continue to play an important
role in the investigation and exploitation of the
spinosyn family of chemistry.
6.8. Conclusion
6: The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance 239
The natural spinosyns produced by select members
of the genus Saccharopolyspora, and their semisynthetic
derivatives, known as spinosoids, constitute a
new and unique class of insect control agents. The
spinosyns possess a novel mode of action, a very
favorable toxicological profile coupled with high
insecticidal efficacy against a broad range of pest
insects, with commercial use focused on the Lepidoptera
and, to a lesser degree, the Diptera. The
commercial fermentation-derived product, spinosad,
is a naturally occurring mixture of spinosyns
A and D, which also happen to be the most insecticidally
active of the natural spinosyns produced by
S. spinosa. While possessing good contact activity,
the spinosyns are most often more active orally, in
part due to the slow cuticular penetration of the
spinosyns compared to many insect control agents.
Although spinosyns A and D are readily metabolized
in vertebrate and avian systems, metabolism
in insects is limited, compensating in part for slow
penetration into insects. The spinosyns cause excitatory
symptoms in insects by stimulating activity in
the CNS. Activation of nondesensitizing nicotinic
acetylcholine receptors by an allosteric mechanism
appears to be the primary mechanism by which
spinosyns stimulate neuronal activity, but antagonism
of an as-yet-unidentified subtype of GABA
receptor may also play a significant role in spinosyn
poisoning. Through an extensive program of strain
selection, genetic manipulation of the biosynthetic
pathways and chemical synthesis, the effects of many
modifications to the forosamine and rhamnose
moieties as well as to the core tetracycle have been
investigated. This experience, with guidance from
classical modeling approaches as well as the application
of QSAR methodologies utilizing artificial
intelligence, has led to the synthesis of spinosoids
with biological activity far exceeding that of spinosyn
A. Because of its unique mode of action and
limited susceptibility to metabolism in insects, pest
insects resistant to other insecticides would typically
not show cross-resistance to spinosad. However, as
expected for any insect control agent put under
heavy selection pressure, resistance to spinosad has
been developed in the laboratory and has also recently
appeared in the field. Available information
suggests that resistance to spinosad is most likely
target-site based, reinforcing the importance of the
IRM recommendations developed by the manufacturer
at the time of its launch that spinosad be used
in rotation with products with other modes of action
to ensure the long-term utility of this novel
chemistry.
Acknowledgments
The authors would like to thank their many colleagues
from Eli Lilly and Co., and Dow AgroSciences
(DAS) who have contributed to our knowledge of
the spinosyns. Special thanks are due to Mr. Jerry
Watson (DAS), Dr Nailah Orr (DAS), Dr Gary
Thompson (DAS), Dr Mark Hertlein (DAS), Dr
Gary Crouse (DAS), Dr Paul Lewer (DAS), and
Dr Ron Mau (University of Hawaii) for their
many helpful discussions during the writing of this
chapter.
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