Developing tools to predict antimicrobial resistance gene and mobile genetic element profiles from metagenomic analysis and demographic data

Lead Research Organisation: King's College London
Department Name: Transplantation Immunology & Mucosal Bio

Abstract

The goal of my PhD is to create a tool to predict the profiles of antimicrobial resistance (AMR) in humans using insights from metagenomic data, and other demographics, such as lifestyle, location and socio-economic status. The PhD will include multiple investigations into different metrics for the prediction tool that can act as independent projects, making this PhD strategy flexible and robust.
The World Health Organisation describes AMR as "one of the biggest threats to global health, food security, and development today". Common bacterial infections are becoming untreatable by antibiotics due to antibiotic resistance, especially in countries such as India and China, where antibiotic over-use and misuse are common. AMR genes have not only been identified from AMR infections, but also in saliva and stool samples from healthy individuals (Diaz-Torres et al., 2006, Pehrsson et al., 2016). Microbes in healthy individuals may acquire AMR genes through: association with mobile genetic elements (MGE) that undergo horizontal gene transfer (HGT) from microbes in the environment, especially from overcrowded living conditions, poor sanitation and farming where antimicrobial drugs are constantly administered to animals; and misuse of antibiotics from a previous infection i.e. not completing the course. Quantifying AMR status of individuals across the globe could have a significant impact on targeting policies most rapidly to those areas with populations at high risk of AMR, for example, earlier surveillance of potential AMR infections and regulating the use of certain antibiotics.
To be able to treat infections quickly and efficiently, health professionals need to prescribe antibiotics that will be completely effective after a first course of treatment. Since AMR is becoming so prevalent, it is important for healthcare professionals to know whether an individual is likely to be at risk of expressing a certain AMR gene and whether this gene could lead to an antibiotic being ineffective against an infection. If this is known, alternative antibiotics or even bacteriophage 1 treatments could be used instead as a first course of treatment. So far, there is no universal profiling tool for AMR. However, research into AMR gene prediction tools and AMR severity scores for worldwide surveillance is already underway by Prof Andrew McArthur and collaborators in Hamilton, Canada, and draft software will be created within the year (personal correspondence). Because of this, I feel it is necessary to focus on a prediction tool that can benefit future diagnosis as well as surveillance.
I plan to create a tool that will aim to predict an individual's AMR profile and association with MGEs based on 1) parameters of microbial diversity: species abundance, richness and co-occurrence, 2) demographics, such as profession and location, and 3) how this information could be applied to antimicrobial resistance diagnosis in the future.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M009513/1 01/10/2015 31/03/2024
1754536 Studentship BB/M009513/1 01/10/2016 30/11/2020 Victoria Carr (Butt)
 
Description Since their discovery in 1928, antibiotics have become a common way of treating infections caused by bacteria, fungi and other microbes. To treat an infection, a doctor usually prescribes a course of antibiotics (such as penicillin) for us to take. This drug is usually contained in a capsule then swallowed, where it dissolves in the stomach.

There, the antibiotic goes to work, destroying all bacteria in the stomach (including the good bacteria, which help our body function). The antibiotic is simultaneously absorbed into the bloodstream, where it is circulated around the body to target any infection present in other body sites, such as the throat or ears. Whether you have an ear or urinary tract infection, the gut is the first point of treatment for bacterial infections.

While antibiotics are helpful to us, a tendency to over-prescribe them is one of the reasons the world faces a crisis of treatment-resistant bacteria. Antibiotic resistance already causes about 700,000 deaths a year - and could cause 10 million deaths by 2050.

Antibiotic resistance happens when bacteria acquire one or several genes that allow them to either destroy or avoid an antibiotic's effects. They does this either by developing mutations in a gene, or acquiring this gene from another microbe.

Resistance then spreads through the body one of two ways. Antibiotics destroy all bacteria - including the ones that protect us from illness and disease. So any bacteria with a genetic mutation or a gene that confers resistance to the antibiotic will be able to reproduce out of control, until it's the main bacterial species present.

Or bacteria can swap their resistance genes with other species of bacteria. In this case, the resistance genes could be given to a new species of bacteria, including the ones that cause disease. This would make treating the infection difficult.

Resistance can also be spread from person to person. For example, a person that has antibiotic-resistant bacteria in their mouth could spread these bacteria to another person simply by coughing or by kissing them.

Until now, scientists have focused research on the gut, seeing it as the main way that antibiotic-resistant bacteria form and spread throughout our bodies. But our latest study shows that we might be tackling antibiotic-resistant bacteria the wrong way.

We discovered for the first time that different sites in the body carry different numbers and species of antibiotic-resistant bacteria. We did this by comparing bacteria in the mouth (which is the first point of entry for antibiotics) with those in the gut (where the antibiotics are released). This discovery will be key for the future of treatment and prevention.
Exploitation Route Given what we're beginning to discover about the sheer variety of bacteria in the human microbiome, to have any hope of stopping the spread of antibiotic resistance scientists need to study the microbiome of different body sites as well.
Sectors Healthcare

URL https://www.nature.com/articles/s41467-020-14422-w
 
Description The Alan Turing Institute
Amount £42,000,000 (GBP)
Funding ID EP/N510129/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2020
 
Title Open-source oral and paired gut metagenomes from RefSeq 
Description Approximately 1200 metagenomes were downloaded as part of a big study look at the difference between antimicrobial resistance profiles between oral and gut. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact Submitted manuscript to high-impact journal 
 
Description The phageome of the human oral cavity and gut 
Organisation University College Cork
Country Ireland 
Sector Academic/University 
PI Contribution I provided data to collaborators. I analysed the data from their pipelines.
Collaborator Contribution Collaborators have run bioinformatic pipelines and provided expertise in bacteriophages
Impact A review paper on the mobilome has been submitted to a high impact journal. Another manuscript is in preparation for submittion to a high impact journal.
Start Year 2018
 
Description Blog for Microbiology Society on Policymaking 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Wrote a blog on a policymaking workshop I attended at the Microbiology Society conference in 2018
Year(s) Of Engagement Activity 2018
URL https://microbiologysociety.org/blog/a-briefing-encounter-with-policymaking.html
 
Description Lightning talk on "Hacking Antimicrobial Resistance" for R-Ladies London meetup 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Gave a lightning talk about how I used coding and R for my research in antimicrobial resistance to a general audience
Year(s) Of Engagement Activity 2018
URL https://www.eventbrite.co.uk/e/r-ladies-lightening-talks-april-2018-tickets-44141919670#
 
Description Organised an evening event on "Innovation in the Microbiome" at King's College London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Organised an evening conference called Innovation in the Microbiome inviting speakers who are experts in the microbiome to give talks, with panel discussion at the end. Also invited media coverage from The Gut Stuff, and radio DJs the Mac Twins.
About 200 people attended this event.
Year(s) Of Engagement Activity 2018
URL https://kcl.inno-forum.org/event/innovation-microbiome/
 
Description Panelist at "HealthTech in Academia: Diverse Leadership & Leaky Pipelines" at University College London 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited panelist for panel discussion and audience Q&A on working in healthtech in academia
Year(s) Of Engagement Activity 2018