The 30 credit specialist module will give you the opportunity to study antimicrobial resistance (AMR), with a particular focus on healthcare impact, genetic technologies, and interventions to reduce AMR. You will explore the major AMR problems, and the strategies needed to reduce the current and future AMR burden.
You will gain insight into how different interventions may be more effective in reducing different AMR pathogens, and will take advantage of active research at St George’s to work on specific topics, including AMR in tuberculosis, MRSA, sexually transmitted infections and HIV.
There will be an opportunity to learn about bioinformatics techniques, new sequencing technologies and ‘omics’ methodologies, and the enormous impact that genetics is having on understanding the epidemiology, selection and evolution of AMR pathogens. There will be a series of sessions focusing on strategies to reduce AMR such as rapid diagnostics, antibiotic stewardship, dosing, new drugs, vaccines and phage applications.
The substantive research project is worth 105 credits. Here are some examples of past student projects.
Evolution in Action: How do MRSA Exchange and Lose Antimicrobial Resistance (AMR) Genes?
Aims: To identify environmental factors and mechanisms that influence AMR gene transfer and gene survival
Brief Overview: Methicillin-resistant Staphylococcus aureus (MRSA) are a major problem in hospitals where they cause a wide variety of difficult to treat infections in immuno-compromised hosts. The major risk factor for MRSA infection is colonisation in the nose, which is the reservoir of infecting isolates. MRSA can be resistant to a wide range of antibiotics, but no isolates carry the full spectrum of resistances. MRSA clones that are highly successful in hospitals adapt to different antimicrobials by exchanging DNA at high frequency, but they must also lose these resistances at high frequency. Using a piglet model of colonization, we have confirmed the very high frequency transfer and loss of mobile genetic elements (MGEs) carrying resistance genes in vivo.
We have also shown that this may be true in colonised humans as we see evidence for high levels of within-host variation in antimicrobial resistance gene carriage in human nasal carriage populations of MRSA. Two previous MRes students have developed in vitro models that allow us to measure resistance gene transfer and loss in conditions mimicking those found in vivo. Transfer and loss of genes is dependent on environmental factors. This project aims to identify environmental factors that are necessary for AMR gene transfer and gene survival. The project will involve co-culturing two distinct isolates of MRSA, each with their own AMR gene marker, and counting the number of double resistant progeny that arise due to gene transfer. A variety of growth media conditions relevant to patient colonisation will be compared. We will then conduct genetic analysis of the pathways involved in transfer and loss, and the method chosen will depend on the preliminary results. This will likely involve gene expression analysis, such as with microarrays, or screening the new Nebraska S. aureus transposon mutant library constructed in the MRSA clonal background of USA300, to identify genes and mechanisms necessary for transfer and loss. By establishing the mechanisms of gene exchange and loss, we will improve our understanding of pathogen evolution and adaptation that can potentially be exploited to reduce the burden of MRSA and AMR, estimated to cost the global economy $100 trillion by 2050.
Modifications on Antimicrobial Peptides to Improve their Performance
Aims: This is a follow-up project and further explores lipidation and glycosylation as tools to overcome some ‘weak’ points of antimicrobial peptides
Brief Overview: With an annual production of about 100,000 tons worldwide, antibiotics have a huge impact on global healthcare and constitute an inherent part of numerous human therapies. However, their wide application, overall availability and consequent overuse has led to the development of resistant strains of pathogenic bacteria with methicillin-resistant Staphylococcus aureus (MRSA) being one of the most prominent examples. Short naturally derived peptides have been demonstrated to be active against a plethora of pathogenic bacteria, fungi, viruses and parasites. Based on their inherent ability to act on various pathogenic microbes with different activities and activity spectra, they appear to be a promising strategy to efficiently target the spreading multidrug resistance. They have various virtues including a facile synthesis, high antimicrobial activity, a multiple mode of action and a fast killing profile. The overall drawback, however, is their low metabolic stability. This results in short circulation half-lifes in a lower minute range. In recent years, various modification strategies have been developed to address metabolic stability and turn peptides into therapeutic agents. Among those, the site-specific attachment of fatty acids (lipidation) and carbohydrates (glycosylation) play a superior role since they have been demonstrated to not only increase peptide stability but also to modulate their biological activity.
Methods used for data collection: The current project aims are the synthesis and in vitro testing of innovative antimicrobial peptides to assess the effect of site-specific lipidation and glycosylation. Different highly active antimicrobial peptides will be chosen from an extensive library, which has been generated by our group, and synthesized by automated solid phase peptide synthesis. By applying orthogonal side-chain protection strategies, different positions within the sequence will be selectively lipidated or glycosylated on-resin via manual coupling. After peptide cleavage from the resin and chromatographic purification the modified peptides will be characterised using liquid chromatography and mass spectrometry. To investigate their antimicrobial activity against different species as well as their cytotoxic profile against human cells, standardised 96-well plate high throughput assays will be used. Additional biological evaluation will focus on comparative mode of action studies using eg flow cytometry. The project provides a highly interdisciplinary work encompassing peptide synthesis and analysis as well as microbiological and human cell culture experiments.