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，鲍曼尼菌细菌是肺炎和亚洲国家其他感染的常见原因。不幸的是，鲍曼尼（A. baumannii）经常引起严重的感染，并且经常对抗生素具有高度耐药性，包括Penems和扩展谱青霉素，并且Baumannii A. a. baumannii感染具有很高的死亡率，需要大量医院资源。我们将研究是否可以将与鲍曼尼曲霉细菌表面结合的抗体用作为鲍曼尼In感染和抗生素的患者提供额外治疗方法。我们将寻找几种抗体疗法的蛋白质靶标，该蛋白可以通过人类白细胞来增加杀死鲍曼尼的杀伤，或者通过抑制抗生素耐药性的机制使以前无效的抗生素能够杀死鲍曼尼a。baumannii。为此，我们将：目标1和2。使用我们最近在300泰nai A. Baumannii菌株的基因含量上获得的信息，以鉴定大多数菌株中存在的蛋白质，并使用这些蛋白质来构建所谓的抗原组阵列。抗原组阵列允许所有引起抗体反应的蛋白质，并且我们将使用鲍曼曲霉保守的蛋白质抗原组阵列来确定哪些蛋白质会引起人或小鼠a。baumanniiA. baumannii感染后的抗体反应。查看哪些基因在感染期间高度表达或抗生素压力细菌时。这些基因应特别好的抗体治疗候选者。AIM4。使用AIMS 1至3中获得的数据来确定应进一步研究哪种鲍曼尼蛋白作为抗体疗法的潜在靶标。我们将制作每种蛋白质抗原，并获得蛋白质的兔抗体，以测试抗体使用免疫功能的实验室测定和感染小鼠模型识别和杀死不同鲍曼尼菌株的能力。从这些数据中，我们选择了一些蛋白抗原用于保护性多价抗体疗法，该抗体靶向几种重要的蛋白质，而不仅仅是个体蛋白抗原作为靶向几种蛋白质的靶向疗法，应使该治疗更有效地作为治疗。IAM5。aim 5。为了确定鲍曼（A. baumannii）感染的患者以及在感染期间，这些患者在感染中可能会从中受益于抗体治疗，我们将收集抗体疗法。此外，我们将纯化这些患者在血液感染模型中使用的抗体，以确认抗体疗法可以抑制血液中的鲍曼尼A. baumannni的生长或对抗生素的耐药性。总体而言，该项目将确定哪种鲍曼尼蛋白会为抗体疗法带来良好的靶标，并确认这种方法在泰国和其他亚洲国家中治疗抗生素抗生素抗生素抗生素的感染的潜力。通过允许从事细菌感染的经验丰富的研究科学家开始研究鲍马尼a。，该项目还将增加研究人员的数量，研究人员的数量，以对抗英国和泰国的抗生素抗生素细菌。

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.