The incidence of mosquito-borne diseases is on the rise - sustained, safe control represents a societal Grand Challenge. In the next five to ten years, scientists must deliver multiple new technologies to control insecticide-resistant mosquitoes. Yet, 50 years after Silent Spring, we still employ “blunt hammer” pesticides that kill helpful, as well as harmful species; concentrate in the environment; and affect human health, inspiring substantial public controversy. An emphasis on screening for molecules that produce lethal end points has stagnated insecticide discovery and contributed to the lack of molecules acting through novel modes of action (MoAs). Our research team seeks to revolutionize vector control through disruptive chemical technologies and improved insecticide control campaigns. We are pursuing novel, non-lethal synthetic chemical tools for precision population suppression of mosquito vectors coupled with new, research-based communications models for optimal response by government officials and the general public during an emergent crisis. Our efforts to re-engineer the phenotypic screening process and effect a paradigm shift in chemical discovery will be presented. Our high content screen (HCS) uses novel phenotypic endpoints to widely explore chemical space and recover unique insect-active molecules that modify mosquito morphology, behavior and development. These “exotic phenotypes,” which have been largely ignored by industrial discovery programs, could reveal new chemistries that operate via modes distinct from existing insecticides. Screen validation was achieved using the Library of Pharmacologically Active Compounds1280 (LOPAC1280) against Aedes aegyptiL1 stage larvae. The screen rapidly differentiated toxic chemistries that operate at neurological targets (i.e., traditional products) from non-toxic chemistries that perturb mosquito behavior and/or fitness (i.e., non-traditional products). Results from our screen of small molecule and natural product (NP) chemistries will be presented. Ongoing work to explore the spectrum of behavioral phenotypes associated with non/sub-lethal “hits” and their impact on mosquito longevity and fecundity will be discussed, as well as efforts to implicate the primary molecular target(s) and determine MoA.

Avoiding silent spring: Revolutionizing vector control by redesigning insecticide discovery and delivery

2019 Fall National Meeting

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