Our approach will reduce reliance on antibiotics and provide an alternative approach based on modifying the body’s immune response that will be active against a range of bacteria, irrespective of their sensitivity to antibiotics.
Background
The treatment of bacterial infection is complicated by antibiotic resistance. The body’s defence against bacteria relies on the immune system and requires blood cells (called macrophages and neutrophils) that eat and kill bacteria. Despite frequent exposure to bacteria that cause serious infections most, people rarely become ill as a result.
We can learn from how the immune system protects most people and develop medicines to “re-engage” the system if it fails. This approach is currently limited by incomplete understanding of the precise mechanisms that kill bacteria in immune cells, but our consortium has made great strides to address this.
Our Work
We now wish to refine our understanding of mechanisms that we have already identified, and supplement this with further experiments to identify the best approaches with which to alter these responses in patients.
Macrophages
In the body, macrophages are the first line of defence against bacteria. We will use techniques that will individually manipulate all of the macrophage’s genes and identify which are most important in regulating bacterial killing. We have also identified that macrophages committing “cell suicide” helps clear bacteria, and we will look for genes that regulate this process.
Neutrophils
When macrophages are overwhelmed by bacteria, neutrophils step in to take over the job. We cannot manipulate the genes of neutrophils, so instead we will use an approach that uses antibodies to target all the proteins in the cell. From this, we will perform a similar screening process to identify the factors that influence bacterial killing.
In particular we want to ensure that we not only enhance bacterial killing, but also that we minimise the chance that immune reactions caused by the targeted neutrophils does not cause damage to the body’s tissues.
Next Steps
Next, we will look at different chemical structures that we think would enhance the selected mechanisms of bacteria killing. We will work with industry partners to adapt these structures for medical use. In particular we will use a new approach called super-resolution microscopy (SRM).
We will modify the chemical structures to ensure our medicines target the right mechanism and location in the macrophage or neutrophil. These compounds will then be tested in our models of bacterial infection, including bacteria that are resistant to multiple antibiotics.
To confirm our findings are relevant to patients and to test potential medicines that we develop we will study macrophages and neutrophils from healthy volunteers or patients at risk of bacterial infection. To achieve this, will use new technologies for fibre optical imaging and unique chemical probes.
We have the potential to translate our findings rapidly into use in patients, as many of the drugs we will use to manipulate the immune response are those already licensed for other medical uses.
SHIELD AMR Research Consortium 