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Adjunct antibody therapy for severe antibiotic-resistant Acinetobacter baumannii infections

严重抗生素耐药鲍曼不动杆菌感染的辅助抗体治疗

基本信息

批准号：
MR/S004394/1
负责人：
Jeremy Brown
金额：
$ 144.91万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS004394%2F1
关键词：
Adjunct antibody therapy severe antibiotic

项目摘要

Unlike in the UK and other Western countries, the bacteria Acinetobacter baumannii is a common cause of pneumonia and other infections in Asian countries. Unfortunately A. baumannii both often causes severe infections and is frequently highly resistant to antibiotics, including penems and extended spectrum penicillins, and A. baumannii infections therefore have a high mortality and require considerable hospital resources. We will investigate whether antibodies that bind to the surface of A. baumannii bacteria could be used as way of providing additional treatment to patients with an A. baumannii infection along with antibiotics. We will look for several protein targets for an antibody therapy that can increase killing of A. baumannii by human white cells or which by inhibiting mechanisms of antibiotic resistance makes a previously ineffective antibiotic able to kill A. baumannii. To do so we will:Aims 1 and 2. Use information that we have recently obtained on the gene content of 300 Thai A. baumannii strains to identify proteins present in most strains, and use these to construct what is called an antigenome array. Antigenome arrays allow all the proteins that cause an antibody response to be identified, and we will use the A. baumannii conserved protein antigenome array to identify which proteins can cause an antibody response after human or mouse A. baumannii infections.Aims 3. Identify which A. baumannii proteins are abundant on the bacteria during infection or in response to antibiotics using a technology called RNAseq to see which genes are highly expressed during infection or when the bacteria has been stressed by antibiotics; these genes should b particularly good candidates for an antibody therapy.Aim 4. Use the data obtained in aims 1 to 3 to identify which A. baumannii proteins should be investigated further as potential targets for an antibody therapy. We will make each protein antigen and obtain rabbit antibodies to the protein to test the ability of the antibody to recognise and kill different A. baumannii strains using laboratory assays of immune function and mouse models of infection. From these data we select a few protein antigens for use in a protective multivalent antibody therapy that targets several important proteins rather than just individual protein antigens as targeting several proteins should make the treatment more effective as a therapy.Aim 5. To identify which patients with A. baumannii infection and when during infection those patients could benefit from an antibody therapy we will collect data on 100 Thai patients with proven A. baumannii infection. In addition we will purify antibodies developing in these patients as a result of the A. baumannii infection for use in our blood infection model to confirm that antibody therapy can inhibit A. baumannni growth in the blood or resistance to antibiotics. Overall the project will identify which A. baumannii proteins would make good targets for an antibody therapy and confirm the potential of this approach for treating antibiotic resistant A. baumannii infections in Thailand and other Asian countries. By allowing experienced research scientists who work on bacterial infections to start investigating A. baumanii as well, the project will also increase the number of researchers investigating how to combat antibiotic resistant bacteria both in the UK and in Thailand.

与英国和其他西方国家不同，鲍曼不动杆菌是亚洲国家肺炎和其他感染的常见病因。不幸的是，鲍曼不动杆菌经常引起严重感染，并且经常对抗生素（包括培南和广谱青霉素）具有高度耐药性，因此鲍曼不动杆菌感染具有高死亡率，需要大量医院资源。我们将研究结合鲍曼不动杆菌表面的抗体是否可以作为鲍曼不动杆菌感染患者与抗生素一起提供额外治疗的方法。我们将寻找抗体治疗的几个蛋白靶点，这些靶点可以增加人类白细胞对鲍曼不动杆菌的杀伤，或者通过抑制抗生素耐药性机制使以前无效的抗生素能够杀死鲍曼不动杆菌。为此，我们将：目标1和目标2。利用我们最近获得的300株泰国鲍曼不动杆菌的基因含量信息来鉴定大多数菌株中存在的蛋白质，并利用这些信息构建所谓的抗基因组阵列。抗基因组阵列允许鉴定所有引起抗体反应的蛋白质，我们将使用鲍曼不动杆菌保守蛋白抗基因组阵列来鉴定人类或小鼠鲍曼不动杆菌感染后哪些蛋白质可以引起抗体反应。目标3。使用一种称为RNAseq的技术来确定哪些鲍曼不动杆菌蛋白在感染期间或对抗生素作出反应时在细菌上丰富，以查看哪些基因在感染期间或细菌受到抗生素胁迫时高度表达；这些基因应该是抗体治疗的特别好的候选基因。目标4。利用目标1至3中获得的数据，确定应进一步研究哪些鲍曼不动杆菌蛋白作为抗体治疗的潜在靶点。我们将制作每种蛋白抗原，并获得兔抗体，通过实验室免疫功能测定和小鼠感染模型测试抗体识别和杀死不同鲍曼不动杆菌菌株的能力。从这些数据中，我们选择了一些蛋白抗原用于针对几种重要蛋白质的保护性多价抗体治疗，而不仅仅是单个蛋白抗原，因为针对几种蛋白质的治疗应该使治疗更有效。目标5。为了确定哪些鲍曼不雅杆菌感染患者以及感染期间这些患者何时可以从抗体治疗中受益，我们将收集100名确诊鲍曼不雅杆菌感染的泰国患者的数据。此外，我们将纯化这些患者由于鲍曼不动杆菌感染而产生的抗体，用于我们的血液感染模型，以证实抗体治疗可以抑制鲍曼不动杆菌在血液中的生长或对抗生素的耐药性。总体而言，该项目将确定哪些鲍曼不动杆菌蛋白将成为抗体治疗的良好靶点，并确认这种方法在泰国和其他亚洲国家治疗耐药鲍曼不动杆菌感染的潜力。通过允许研究细菌感染的有经验的科学家也开始研究鲍曼不动杆菌，该项目还将增加英国和泰国研究如何对抗抗生素耐药细菌的研究人员的数量。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sequential Vaccination With Heterologous Acinetobacter baumannii Strains Induces Broadly Reactive Antibody Responses.

DOI：
10.3389/fimmu.2021.705533
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Kamuyu G;Suen Cheng Y;Willcocks S;Kewcharoenwong C;Kiratisin P;Taylor PW;Wren BW;Lertmemongkolchai G;Stabler RA;Brown J
通讯作者：
Brown J

Streptococcus pneumoniae meningitis and the CNS barriers.