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

• 批准号: 10606624
• 负责人: Linden T Hu
• 金额: $ 75.41万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 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/10606624
• 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; Experimental Designs; Exposure to; Financial cost; Food; Formulation; Genes; Geographic Distribution; Geography; Goals; Growth; Habitats; Health; Human; Incidence; Infection; Infection Control; Ingestion; Island; Ixodes; Laboratories; Lead; Lyme Disease; Mammals; Manufacturer; Marketing; Massachusetts; Measures; Modification; Mus; Oral; Oral Administration; Organism; OspA protein; Peptidyltransferase; Peromyscus; Pharmacodynamics; Politics; Population; Population Control; Public Health; Recombinant Proteins; Recovery; Resistance; Resistance development; Resources; Ribosomes; Rocky Mountain Spotted Fever; Rodent; Safety; Salmonella; Soil; Source; Specificity; Streptomyces; Test Result; Testing; Therapeutic; Ticks; Tilia; Toxic effect; United States; Vaccination; Vaccines; acaricide; disorder control; dosage; drug development; efficacy evaluation; 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; transmission process; uptake; vector; vector tick; weapons; whole genome

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.

莱姆病在美国的发病率和地理分布自第一次莱姆病以来一直在稳步上升 1977年的描述。通过控制扁虱的数量来阻止疾病传播的努力 病媒和/或小鼠宿主仅取得了有限的成功。唯一被批准的 用于预防莱姆病的人类疫苗被制造商进一步下架 强调了控制疾病的新方法的必要性。 在这个项目中，我们建议开发一种针对老鼠和扁虱的新型抗生素。 疾病的蓄水池。这项建议结合了金·刘易斯博士在药物开发方面的专业知识 实验室，林登·胡博士实验室的伯氏疏螺旋体生物学专业知识和 萨姆·特尔福德博士的实验室。用抗生素多西环素治疗小鼠已被证明是高度有效的。 有效地根除了伯氏疏螺旋体的水库宿主。然而，人们有理由担心 伯氏杆菌和其他可能接触抗生素的生物体的抗药性发展 它是否应该被广泛分布。多西环素是一种治疗多发性人类疾病的重要抗生素。 感染，在某些情况下，如无浆体或落基山斑疹热，唯一获得批准的药物 可用。我们已经确定了一种抗生素，潮霉素A(HygA)，它对伯氏杆菌有很高的活性，但 对其他人类病原体的活性有限。它的作用机制不同于其他人类 抗生素。在我们的初步数据中，我们已经表明它对清除伯氏杆菌是非常有效的。 通过灌胃或以诱饵配方口服时感染的小鼠。在本提案中，我们将完成以下步骤 将HygA开发为一种环境抗生素，并在日本近海的一个孤岛上进行有限的田间试验 马萨诸塞州海岸，以测试其控制扁虱和老鼠感染率的能力。 在目标1中，我们将建立HygA在Permyscus小鼠体内的药效学、稳定性和安全性。 我们将确定最佳投饵浓度，并进行投饵模拟研究。 以及笼养动物的通关。在目标2中，我们将尝试诱导伯氏杆菌和 在环境中可能遇到HygA的其他对人类重要的生物。我们会确认 如果对HygA产生耐药性，它不会对人类对其他抗生素产生耐药性 申请。最后，在目标3中，我们将在一个孤岛上进行有限的实地试验，该孤岛是B。 在扁虱和小鼠中建立一种以HygA为基础的贮存库靶向抗生素的有效性。 这项研究有可能对人类莱姆病产生重大影响，因为它控制了 它的主要水库。通过使用一种活性范围很窄的抗生素，这种抗生素没有人类 应用，我们希望复制多西环素的成功，它可以说是最成功的 到目前为止，尝试任何环境根除方法，而不会产生耐药性。

项目成果

Development of a capture sequencing assay for enhanced detection and genotyping of tick-borne pathogens.

开发捕获测序测定法，加强蜱媒病原体的检测和基因分型。

• DOI: 10.1038/s41598-021-91956-z
• 发表时间: 2021-06-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jain K;Tagliafierro T;Marques A;Sanchez-Vicente S;Gokden A;Fallon B;Mishra N;Briese T;Kapoor V;Sameroff S;Guo C;Marcos LA;Hu L;Lipkin WI;Tokarz R
• 通讯作者: Tokarz R