Mosquito-borne diseases such as Zika, Chikungunya, and West Nile Virus are on the rise in the United States and, as the dominant vector for malaria, mosquitoes continue to contribute to the death of approximately one million people worldwide each year. New approaches for control of the mosquito vector are in crucial need, but major challenges to mosquito-control deal with challenges of insuring human safety, limiting off-target effects in the ecosystem, and opposing resistance. To meet these challenges, a novel cell-based screening platform was used to identify lead compounds with the potential to safely and specifically eliminate this disease vector. Our marine bacteria-derived library of natural products (NPs) was screened to systematically search for compounds that were lethal to cultured mosquito cells but showed negligible activity against human or other insect cell lines. A novel boron-containing macrolide, “NP-34,” derived from a strain of Streptomyces was determined to be a selective mosquito toxin. In cell-based screening of NP-34, exposure led to approximately 80% cell death in mosquito derived cell lines whereas control cell lines were unaffected; this phenotype was observed when repeated with larvae and adult mosquitoes. Since NP-34 is a promising compound for the development of a novel, human-safe, and eco-friendly insecticide, we are currently in efforts of isolating B-containing macrolides from bacterial-fermentations. In addition to isolating naturally occurring analogs, we aim to semi-synthetically functionalize analogs, based on initial studies, in effort to reap the most toxic and most selective NP. Our future goals are to study NP-34 with biotin-strepavidin based target ID pulldowns within the mosquito vector. Additionally, since host species isolation results in miniscule quantities of NP-34, our near-future goal is to heterologously express the biosynthetic gene cluster (BGC) in yeast in efforts to maximize production of these B-containing macrolides. Recently, the genome of our Streptomyces strain has been sequenced, yielding our proposed BGC responsible for NP-34 production which is currently being validated via knock-out experiments. Since NP-34 has poor UV-activity, 11-B NMR and ICP-MS methods are being developed in efforts to quantify production of B-containing macrolides with this expression.

Discovery of a novel, boron-containing macrolide as a mosquito-specific toxin for insecticide development

2019 Fall National Meeting

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