Project Summary Mosquito borne pathogens afflict millions of people worldwide and their prevalence is anticipated toincrease as mosquitoes and their pathogens become resistant to currently available drugs and insecticides.While drugs can be used to treat some mosquito borne pathogens a majority of transmission control comesthrough targeting the mosquito vector itself. While insecticides targeting both adult and larval stages areavailable larvicides have the advantage of targeting a constrained target that is unable to readily evadetreatment. Unfortunately only a few larvicides are available for use and their modes of action are limited.Thus there is a critical need for selective novel larvicides with additional modes of action. We have developedtwo novel delivery systems that target the uniquely high pH levels of the larval gut. We hypothesize thatprovisioning these compounds to immature mosquitoes will allow us to induce lethal effects in mosquitoes ofmedical importance. Through a recursive set of aims whereby compounds are readily synthesized tested andevaluated we will test this hypothesis in two important mosquito vectors the malaria vector Anophelesstephensi and the arboviral vector Aedes aegypti. In Specific Aim 1 we assess the activity of pH responsivecompounds that are tuned to the unique larval midgut environments of Aedes aegypti and Anophelesstephensi mosquitoes. An initial set of compounds developed by our lab in the MaMa and PTBD classes will beprovisioned to larvae and their efficacy will be assess through SDS-PAGE imaging and proteomic studies. InSpecific Aim 2 we will determine the ability of pH sensitive compounds to negatively impact larvaldevelopment and deliver larvicidal compounds specifically to the midgut of immature mosquitoes. Compoundsdeveloped to perturb the larval gut will be evaluated for any deleterious effects that they have on the mosquito.In depth studies of their metabolism membrane integrity and larval and adult fitness will be conducted. By theend of this study we will have assessed the activity of two chemically distinct sets of compounds in the midgutof larval mosquitoes. The long-term goal is to develop flexible and highly mosquito-specific larvicidalcompounds with the capacity to leverage unique modes of action.