Development and Field Testing of a Novel Reservoir Targeted Antibiotic Against Borrelia burgdorferi

新型水库靶向伯氏疏螺旋体抗生素的开发和现场测试

基本信息

批准号：
10165497
负责人：
Linden T Hu
金额：
$ 72.04万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10165497
关键词：
Anaplasma Anaplasma phagocytophilum Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Area Awareness Bacteria Biology Borrelia burgdorferi Clinical Collaborations Data Deer Development Diagnosis Disease Disease Reservoirs Dose Doxycycline Drug Kinetics Eating Environment Evaluation Excision Exposure to Financial cost Food Formulation Genes Geographic Distribution Geography Goals Growth Habitats Health Human Incidence Infection Infection Control Ingestion Island Ixodes Laboratories Lead Life Lyme Disease Mammals Manufacturer Name Massachusetts Measures Modification Mus Oral Oral Administration Organism OspA protein Peptidyltransferase Peromyscus Pharmacodynamics Politics Population Public Health Recombinant Proteins Recovery Resistance Resistance development Resources Ribosomes Rocky Mountain Spotted Fever Rodent Safety Salmonella Soil Source Specificity Streptomyces Test Result Testing Ticks Tilia Toxic effect United States Vaccination Vaccines acaricide base design dosage drug development experimental study exposed human population field study genome sequencing human disease human pathogen hygromycin A infection rate inhibitor/antagonist microorganism mutant novel novel strategies pathogen simulation stem success tool uptake vector vector tick weapons whole genome

项目摘要

The incidence and geographic distribution of Lyme disease in the U.S. has increased steadily since its first description in 1977. Efforts to stem the spread of the disease through controlling the population of its tick vector and/or the mouse reservoirs of the disease have met with only limited success. The only approved human vaccine to protect against Lyme disease was removed from the market by its manufacturer further highlighting the need for new approaches to controlling the disease. In this project, we propose the development of a novel antibiotic targeted towards the mouse and tick reservoirs of the disease. This proposal combines the expertise in drug development of Dr. Kim Lewis’ laboratory, the expertise in Borrelia burgdorferi biology in Dr. Linden Hu’s laboratory and the field expertise of Dr. Sam Telford’s laboratory. Treatment of mice with an antibiotic, doxycycline, has been shown to be highly effective in eradicating Borrelia burgdorferi from its reservoir hosts. However, there is legitimate concern for development of resistance, both in B. burgdorferi and in other organisms that may be exposed to the antibiotic should it be widely distributed. Doxycyline is an important antibiotic in the treatment of multiple different human infections and in some cases such as Anaplasma or Rocky Mountain Spotted Fever, the only approved agent available. We have identified an antibiotic, hygromycin A (HygA), that is highly active against B. burgdorferi but has limited activity against other human pathogens. Its mechanism of action is different from other human antibiotics. In our preliminary data, we have shown that it is very effective in clearing B. burgdorferi from infected mice when given orally by gavage or in bait formulations. In this proposal, we will complete the steps in developing HygA as an environmental antibiotic and perform a limited field trial on an isolated island off the coast of MA to test its ability to control infection rates in ticks and mice. In Aim 1, we will establish the pharmacodynamics, stability and safety profile of HygA in Peromyscus mice. We will determine optimum concentrations for bait distribution and perform simulation studies of bait uptake and clearance in caged animals. In Aim 2, we will attempt to induce resistance to HygA in B. burgdorferi and in other organisms of human importance that are likely to encounter HygA in the environment. We will confirm that if HygA resistance develops, it does not cause concomitant resistance to other antibiotics with human applications. Finally, in Aim 3, we will perform a limited field trial on an isolated island that is endemic for B. burgdorferi in ticks and mice to establish the efficacy of a HygA based reservoir targeted antibiotic approach. This study has the potential to have a major impact on human Lyme disease by controlling the organism in its major reservoirs. By utilizing an antibiotic that has a narrow spectrum of activity and does not have human applications, we hope to replicate the success seen with doxycycline, which is arguably the most successful trial of any environmental approach to eradication to date, without the attendant concerns for resistance.

自首次发行以来，美国莱姆病的事件和地理分布一直在稳步增长描述在1977年。通过控制其tick的人群来阻止疾病的传播。疾病的载体和/或小鼠储备仅取得了有限的成功。唯一的批准人类疫苗预防莱姆病的疫苗进一步从市场上取出强调需要控制这种疾病的新方法。在这个项目中，我们提出了针对鼠标的新型抗生素的开发，并提出了滴答作用。该疾病的水库。该建议结合了金·刘易斯博士的药物开发专业知识实验室，林登胡（Linden Hu Sam Telford博士的实验室。用抗生素强力霉素治疗小鼠，已被证明是高度的有效地从其储层托管中消除了Borrelia Burgdorferi。但是，有合理的关注抗药性的抗药性和其他可能暴露于抗生素的生物体中的抗性发展是否应该广泛分布。多西环林是治疗多种不同人类的重要抗生素感染，在某些情况下，例如齿状或落基山斑点发烧，是唯一的批准的特工可用的。我们已经确定了一种抗生素A（Hyga），对B. burgdorferi具有很高的活性对其他人类病原体的活性有限。它的作用机制与其他人不同抗生素。在我们的初步数据中，我们表明它在清除B. burgdorferi中非常有效口服时，被感染的小鼠在口服或诱饵公式中。在此提案中，我们将完成步骤在开发hyga作为一种环境抗生素时，并在一个孤立的岛屿上进行了有限的现场试验 MA海岸测试其控制壁虱和小鼠感染率的能力。在AIM 1中，我们将在Peromysscus小鼠中建立Hyga的药效学，稳定性和安全性。我们将确定诱饵吸收的诱饵分布和性能模拟研究的最佳浓度和笼中动物的清除。在AIM 2中，我们将试图在B. B. B. B. B.和In中引起对Hyga的抵抗其他具有人类重要性的生物可能会在环境中遇到hyga。我们将确认如果hyga耐药性发展，它不会引起对其他人类对其他抗生素的耐药性申请。最后，在AIM 3中，我们将在一个孤立的岛屿上进行有限的现场试验，该岛是B的内在。在壁虱和小鼠中的伯格德菲利（Burgdorferi）建立了基于hyga的储层靶向抗生素方法的效率。这项研究有可能通过控制生物体中的生物来对人类莱姆病产生重大影响它的主要水库。通过使用具有狭窄活性且没有人类的抗生素应用程序，我们希望复制用多西环素（Doxycycline）看到的成功，这可以说是最成功的迄今为止，任何环境方法的辐射方法的试验，而无需担心阻力。