Adjunct antibody therapy for severe antibiotic-resistant Acinetobacter baumannii infections

点击翻译按钮获取中文摘要

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.