The epidemiology of transmissible antimicrobial resistance among Shigella species
Lead Research Organisation:
University of Cambridge
Department Name: Department of Genetics
Abstract
Antimicrobial drugs, such as antibiotics, antivirals and antifungals, revolutionised medicine. They are essential for fighting diseases, and make surgery and cancer therapies safer. Unfortunately, many of the microbes which these drugs fight are becoming 'resistant' and the antimicrobial drugs no longer work. Worldwide, more than 700,000 people each year die due to antimicrobial drug-resistant disease. Antimicrobial resistance (AMR) is increasing rapidly; the United Nations predicts that number of deaths due to antimicrobial drug-resistant disease may climb to as many as 10 million deaths per year by 2050 if no action is taken.
Our work focuses on AMR in Shigella bacteria. Shigella are the main cause of severe diarrhoea among children in low-and middle-income countries and also cause sexually transmissible illness in men who have sex with men. Over 200 million people become ill from Shigella each year and over 200,000 people die. There is no widely available vaccine against Shigella and, like many other bacteria, they are becoming resistant to antimicrobials. The World Health Organisation list Shigella as one of twelve priority organisms for antimicrobial resistance (AMR).
When bacteria reproduce, they typically divide into two daughter cells. The process by which AMR genes are passed from parent to daughter cells is well understood and monitored. However, many bacterial species are also able to transfer genes for AMR between different cells using mobile genetic elements (MGEs). This is called 'transmissible AMR' and - as the name suggests - involves direct transfer of genes between two bacteria. Our pilot work shows that about half of the AMR in Shigella is transmissible. We don't fully understand how MGEs move about in bacterial populations, but it is clear that some AMR-MGEs stay in bacteria which go on to cause lots of infections, while others don't.
Understanding how AMR MGEs spread amongst bacterial populations, and which MGEs will be successful is challenging; we need to consider the AMR gene, the MGE, the bacteria, and the human hosts. Shigella is an excellent model to study transmissible AMR because Shigella infections are already tracked by national public health surveillance teams, and because it only causes infections in humans (so we don't need to consider the effects of different hosts). This means that we can use routine surveillance data to understand how the bacteria and the human hosts interact.
This project will, for the first time, create a global overview of the most important Shigella bacteria in their human hosts. It will characterise all the MGEs carrying medically important AMR to understand which ones are causing the most infections and how the MGEs are moving through the bacterial populations. We will then study which types, and what features, of MGEs are the most important factors for driving this transmissible AMR in the real-world. This will enable us to understand the biology of AMR-MGEs and identify features that might act as 'early warning signs' for the emergence of new AMR bacteria.
We want our research to make health systems better by identifying newly emerging AMR and understanding which groups of people are at most risk from Shigella AMR. In the future this will enable these people to be given specialised healthcare, such as screening and tailored antimicrobial recommendations. We have built a team that includes academic researchers specialising in AMR and public health specialists who are responsible for disease surveillance across four countries. This will ensure that our new findings and new approaches are useful for public health practitioners and that they will be adopted for use in real-world settings in the near term. Although this project focuses on Shigella, our new methods will be designed to make them easy to use for other bacterial species in the future.
Our work focuses on AMR in Shigella bacteria. Shigella are the main cause of severe diarrhoea among children in low-and middle-income countries and also cause sexually transmissible illness in men who have sex with men. Over 200 million people become ill from Shigella each year and over 200,000 people die. There is no widely available vaccine against Shigella and, like many other bacteria, they are becoming resistant to antimicrobials. The World Health Organisation list Shigella as one of twelve priority organisms for antimicrobial resistance (AMR).
When bacteria reproduce, they typically divide into two daughter cells. The process by which AMR genes are passed from parent to daughter cells is well understood and monitored. However, many bacterial species are also able to transfer genes for AMR between different cells using mobile genetic elements (MGEs). This is called 'transmissible AMR' and - as the name suggests - involves direct transfer of genes between two bacteria. Our pilot work shows that about half of the AMR in Shigella is transmissible. We don't fully understand how MGEs move about in bacterial populations, but it is clear that some AMR-MGEs stay in bacteria which go on to cause lots of infections, while others don't.
Understanding how AMR MGEs spread amongst bacterial populations, and which MGEs will be successful is challenging; we need to consider the AMR gene, the MGE, the bacteria, and the human hosts. Shigella is an excellent model to study transmissible AMR because Shigella infections are already tracked by national public health surveillance teams, and because it only causes infections in humans (so we don't need to consider the effects of different hosts). This means that we can use routine surveillance data to understand how the bacteria and the human hosts interact.
This project will, for the first time, create a global overview of the most important Shigella bacteria in their human hosts. It will characterise all the MGEs carrying medically important AMR to understand which ones are causing the most infections and how the MGEs are moving through the bacterial populations. We will then study which types, and what features, of MGEs are the most important factors for driving this transmissible AMR in the real-world. This will enable us to understand the biology of AMR-MGEs and identify features that might act as 'early warning signs' for the emergence of new AMR bacteria.
We want our research to make health systems better by identifying newly emerging AMR and understanding which groups of people are at most risk from Shigella AMR. In the future this will enable these people to be given specialised healthcare, such as screening and tailored antimicrobial recommendations. We have built a team that includes academic researchers specialising in AMR and public health specialists who are responsible for disease surveillance across four countries. This will ensure that our new findings and new approaches are useful for public health practitioners and that they will be adopted for use in real-world settings in the near term. Although this project focuses on Shigella, our new methods will be designed to make them easy to use for other bacterial species in the future.
Technical Summary
Much of the AMR among Shigella, and other bacterial pathogens, is transmissible through the transfer of AMR-containing mobile genetic elements (e.g. plasmids) whose real-world epidemiology in bacterial populations is poorly understood. As an established, highly visible, obligate pathogen, Shigella represents an ideal denominator population for characterising, and understanding transmissible AMR. We will leverage these unique features and develop new methodology to:
WP1: Construct epidemiologically compartmentalised global denominator populations of Shigella and characterise the nature, and distribution, of AMR-MGEs across them. Phylogenetic reconstruction, AMR gene detection, and ancestral state reconstruction of 7500 genomes from public health surveillance, with complementary long-read sequencing of 800 isolates, will reconstruct a global genomic portrait of Shigella AMR and the MGEs that carry it.
WP2: Determine the emergence rates of AMR-MGEs to understand their relative importance in driving AMR emergence. Temporal reconstruction of the phylogenies will facilitate calculation of novel phylodynamic-aware metrics of AMR occurrence. We will develop multilevel statistical models to predict AMR emergence incorporating pathogen genetic and host factors, thus determining the relative importance of AMR-MGEs.
WP3: Identify which genotypic and phenotypic features of AMR-MGEs drive clinically relevant AMR emergence. Using in vitro screening and plasmid GWAS we will identify MGE factors associated with AMR emergence. This will identify phenotypes and genetic markers that may be early predictors of AMR emergence.
WP4: Identify early predictors of AMR emergence within public health surveillance to facilitate timely intervention. Working with our public health project partners, we will advance surveillance of transmissible AMR through adapting WP2 to hierarchical clustering population structures and for database-agnostic detection of rapidly emerging genes.
WP1: Construct epidemiologically compartmentalised global denominator populations of Shigella and characterise the nature, and distribution, of AMR-MGEs across them. Phylogenetic reconstruction, AMR gene detection, and ancestral state reconstruction of 7500 genomes from public health surveillance, with complementary long-read sequencing of 800 isolates, will reconstruct a global genomic portrait of Shigella AMR and the MGEs that carry it.
WP2: Determine the emergence rates of AMR-MGEs to understand their relative importance in driving AMR emergence. Temporal reconstruction of the phylogenies will facilitate calculation of novel phylodynamic-aware metrics of AMR occurrence. We will develop multilevel statistical models to predict AMR emergence incorporating pathogen genetic and host factors, thus determining the relative importance of AMR-MGEs.
WP3: Identify which genotypic and phenotypic features of AMR-MGEs drive clinically relevant AMR emergence. Using in vitro screening and plasmid GWAS we will identify MGE factors associated with AMR emergence. This will identify phenotypes and genetic markers that may be early predictors of AMR emergence.
WP4: Identify early predictors of AMR emergence within public health surveillance to facilitate timely intervention. Working with our public health project partners, we will advance surveillance of transmissible AMR through adapting WP2 to hierarchical clustering population structures and for database-agnostic detection of rapidly emerging genes.
