Disrupting the mosquito larval midgut using novel pH responsive compounds

使用新型 pH 响应化合物破坏蚊子幼虫中肠

• 批准号: 10722596
• 负责人: John C Jewett
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722596
• 关键词: Acetylcholinesterase Inhibitors; Acids; Adult; Aedes; Affect; Anopheles Genus; Anterior; Arboviruses; Bacillus; Bacillus thuringiensis; Binding; Biotin; Cessation of life; Chemicals; Classification Scheme; Culicidae; Detection; Development; Environment; Frequencies; Goals; Habitats; Image; Insecta; Insecticide Resistance; Insecticides; Juvenile Hormones; Larva; Life; Link; Lysine; Malaria; Medical; Membrane; Metabolism; Methoprene; Microscopy; Midgut; Mosquito Control; Nicotinic Receptors; Organism; Persons; Pharmaceutical Preparations; Poison; Population; Prevalence; Proteins; Proteomics; Reaction; Resistance; Resistance development; Specificity; System; Techniques; Temephos; Testing; Time; Tyrosine; Western Blotting; cost; cytochemistry; fitness; flexibility; fluorophore; microbial; mosquito-borne pathogen; novel; pathogen; receptor; tool; transmission process; vector; vector mosquito

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.

项目摘要 苔藓传播的病原体折磨着全世界数百万人，预计它们的流行率将 随着蚊子及其病原体对现有药物和杀虫剂产生抗药性， 虽然药物可以用来治疗一些蚊子传播的病原体，但大多数传播控制来自于 通过攻击蚊子载体本身。虽然针对成虫和幼虫阶段的杀虫剂 现有的杀幼虫剂具有针对无法轻易躲避的受限制目标的优点 治疗不幸的是，只有少数杀幼虫剂可供使用，而且它们的作用方式也有限。 因此，迫切需要具有额外作用模式的选择性新型杀幼虫剂。我们已经开发 两种新型的输送系统，目标是幼虫肠道的独特高pH值水平。我们假设 将这些化合物提供给未成熟的蚊子将使我们能够在蚊子中诱导致命效果， 医学重要性通过一套递归的目标，化合物很容易合成，测试和 我们将在两种重要的蚊媒中检验这一假设， stephensi和虫媒病毒载体埃及伊蚊。在具体目标1中，我们评估了pH响应的活性， 埃及伊蚊和按蚊独特的幼虫中肠环境的化合物 斯蒂芬蚊子。我们的实验室在MaMa和PTBD类中开发的最初一组化合物将是 提供给幼虫，并通过SDS-PAGE、成像和蛋白质组学研究评估其功效。在 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特异性地递送至未成熟蚊子的中肠。化合物 将评估所开发的干扰幼虫肠道的药物对蚊子的任何有害影响。 将对它们的代谢、膜完整性以及幼虫和成虫的适应性进行深入研究。由 在本研究的最后，我们将评估两组化学上不同的化合物在中肠中的活性 蚊子的幼虫长期目标是开发灵活的和高度蚊子特异性的杀幼虫剂 具有利用独特作用模式的能力的化合物。