Disrupting the mosquito larval midgut using novel pH responsive compounds

项目摘要 蚊子传播的病原体折磨着全球数百万人，它们的流行预计将 随着蚊子及其病原体对现有药物和杀虫剂产生抗药性而增加。 虽然药物可以用来治疗一些蚊子传播的病原体，但大多数传播控制 通过以蚊子媒介本身为目标。而针对成虫和幼虫的杀虫剂是 在现有条件下，杀幼虫剂的优势是瞄准一个无法轻易躲避的受限目标。 治疗。不幸的是，只有少数几种杀幼虫剂可供使用，其作用模式有限。 因此，迫切需要具有更多作用模式的选择性新型杀幼虫剂。我们已经开发出 两个新的递送系统，目标是幼虫肠道独特的高pH水平。我们假设 将这些化合物供应给未成熟的蚊子将使我们能够对蚊子产生致命的影响 医学上的重要性。通过递归的一系列目标，化合物易于合成、测试和 我们将在两个重要的蚊子媒介--疟疾媒介按蚊中测试这一假说。 Stephensi和虫媒埃及伊蚊。在特定目标1中，我们评估pH响应的活性 适应埃及伊蚊和按蚊独特的幼虫中肠环境的化合物 斯氏蚊子。我们实验室在MAMA和PTBD课程中开发的第一套化合物将是 将通过SDS-PAGE、成像和蛋白质组学研究来评估其有效性。在……里面 具体目标2我们将确定pH敏感化合物对幼虫产生负面影响的能力 开发并将杀幼虫化合物专门输送到未成熟蚊子的中肠。化合物 为了扰乱幼虫的肠道，将对它们对蚊子的任何有害影响进行评估。 将对它们的新陈代谢、膜完整性以及幼虫和成虫的健康状况进行深入研究。由 在这项研究结束时，我们将评估中肠中两组不同化学成分的活性。 幼虫蚊子。长期目标是开发灵活的、高度针对蚊子的杀幼虫 具有利用独特行动模式的能力。

Project Summary Mosquito borne pathogens afflict millions of people worldwide and their prevalence is anticipated to increase 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 comes through targeting the mosquito vector itself. While insecticides targeting both adult and larval stages are available, larvicides have the advantage of targeting a constrained target that is unable to readily evade treatment. 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 developed two novel delivery systems that target the uniquely high pH levels of the larval gut. We hypothesize that provisioning these compounds to immature mosquitoes will allow us to induce lethal effects in mosquitoes of medical importance. Through a recursive set of aims whereby compounds are readily synthesized, tested and evaluated we will test this hypothesis in two important mosquito vectors, the malaria vector Anopheles stephensi and the arboviral vector Aedes aegypti. In Specific Aim 1 we assess the activity of pH responsive compounds that are tuned to the unique larval midgut environments of Aedes aegypti and Anopheles stephensi mosquitoes. An initial set of compounds developed by our lab in the MaMa and PTBD classes will be provisioned to larvae and their efficacy will be assess through SDS-PAGE, imaging, and proteomic studies. In Specific Aim 2 we will determine the ability of pH sensitive compounds to negatively impact larval development and deliver larvicidal compounds specifically to the midgut of immature mosquitoes. Compounds developed 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 the end of this study, we will have assessed the activity of two chemically distinct sets of compounds in the midgut of larval mosquitoes. The long-term goal is to develop flexible and highly mosquito-specific larvicidal compounds with the capacity to leverage unique modes of action.