As vectors of both parasitic and viral diseases, endemic mosquito populations are a global concern. In Africa, mosquitoes contribute to at least one million deaths each year and, here in the United States, mosquito-borne diseases are also on the rise. Strategies for mitigating transmission of these diseases require the use of insecticides but conventionally applied agents lack specificity and lose efficacy as resistance inevitably emerges. Consequently, there is an urgent need to develop new agents that are narrowly targeted, environmentally harmless and safe to humans. Traditional searches for new insecticides involve whole animal screening but, unfortunately, these approaches sample compounds on very limited scales and lack environmental safety tests early in the pipeline. Furthermore, rationale design principles commonly leveraged for drug development programs have not been routinely exploited for pesticide development. To address these limitations, we recently conducted a pilot study to test the feasibility of an alternative discovery platform. Specifically, we examined whether cell-based screens and counterscreens could be leveraged as a surrogate to identify targeted, vector-specific toxins when tested in whole animals. Towards this goal, we designed a high throughput platform that systematically searches for compounds that are lethal to cultured mosquito cells but show negligible activity against human, rodent or other insect cell lines. Our strategy captured a rare set of compounds that specifically killed mosquito cells and, importantly, targeted killing in culture was associated with selective toxicitis in whole animal assays. Furthermore, where tested, strains resistant to a commonly used insecticide (pyrethroid) were also susceptible. Taken together, our results demonstrate that capabilities enabled by this platform dramatically outperform whole animal screens and can expose untapped mosquito specific vulnerabilities. We wish to capitalize on this proof-of-concept to deliver the most potent and most selective mosquitocides obtainable from massive chemical and natural product libraries. Our initiative is ideally suited for R21 support and we expect compelling outcomes. Specifically, we estimate discovery of approximately 20 lead compounds for environmentally safe, mosquito-specific toxicants. This collection will establish a novel foundation for programs directed towards chemical optimization and advanced field-testing. At the same time, outcomes here will also present unique opportunities to probe mosquito-specific vulnerabilities through target identification efforts. Our methodical platform is highly adaptable. Therefore, a successful precedent here could inspire similar efforts to develop customized pesticides that target other disease vectors as well.
Mosquitoes are a relentless threat to global health because they are vectors for devastating diseases, such as West Nile Virus and malaria. To effectively combat these and other mosquito-borne diseases, new pesticides that are narrowly targeted and safe to humans are urgently needed. This initiative applies an innovative discovery platform to identify novel and highly targeted compounds for controlling this disease vector.
