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：
10674121
负责人：
Linden T Hu
金额：
$ 21.89万
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/10674121
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 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.

自莱姆病首次出现以来，美国莱姆病的发病率和地理分布一直在稳步增加 1977 年的描述。通过控制蜱虫数量来阻止疾病传播该疾病的媒介和/或小鼠宿主仅取得了有限的成功。用于预防莱姆病的人类疫苗进一步被制造商从市场上撤下强调需要新方法来控制该疾病。在这个项目中，我们建议开发一种针对小鼠和蜱的新型抗生素该提案结合了 Kim Lewis 博士在药物开发方面的专业知识。实验室、Linden Hu 博士实验室的伯氏疏螺旋体生物学专业知识以及萨姆·特尔福德博士的实验室用抗生素强力霉素治疗小鼠的效果非常好。可以有效地从其储存宿主中根除伯氏疏螺旋体。然而，人们对它的担忧是合理的。伯氏疏螺旋体和其他可能接触抗生素的生物体中出现耐药性强力霉素是治疗多种不同人类的重要抗生素。感染，以及在某些情况下，例如无形体或落基山斑疹热，这是唯一批准的药物我们已经鉴定出一种抗生素潮霉素 A (HygA)，它对伯氏疏螺旋体具有高度活性，但对其他人类病原体的活性有限，其作用机制与其他人类病原体不同。我们的初步数据表明，它对于清除伯氏疏螺旋体非常有效。通过灌胃或诱饵制剂口服给药时感染的小鼠，我们将完成以下步骤。开发 HygA 作为一种环境抗生素，并在离岛不远的一座孤岛上进行了有限的现场试验马萨诸塞州海岸，测试其控制蜱虫和小鼠感染率的能力。在目标 1 中，我们将建立 HygA 在 Peromyscus 小鼠中的药效学、稳定性和安全性特征。我们将确定诱饵分布的最佳浓度并进行诱饵吸收的模拟研究在目标 2 中，我们将尝试在伯氏疏螺旋体和中诱导对 HygA 的抗性。我们将确认可能在环境中遇到 HygA 的其他对人类重要的生物体。如果 HygA 产生耐药性，不会导致人类对其他抗生素同时产生耐药性最后，在目标 3 中，我们将在 B. 伯氏杆菌在蜱虫和小鼠体内建立了基于 HygA 的靶向抗生素方法的功效。这项研究有可能通过控制体内的生物体对人类莱姆病产生重大影响它的主要储存库是利用活性谱窄且对人类无害的抗生素。我们希望复制多西环素的成功，这是有争议的最成功的药物迄今为止，对任何环境根除方法进行的尝试，都没有随之而来的耐药性问题。