Antibiotic Discovery in the Abyss

By Dr Paul Race, Senior Lecturer, School of Biochemistry, University of Bristol.

Global health

Deep sea coral and fishThe development of antibiotics is considered by many to be the greatest medical advancement in human history. Recently, however, the emergence of antimicrobial resistance (AMR) as a global threat to our health and wellbeing has brought into sharp focus the pressing need for the discovery and development of new antibiotics capable of overcoming the impending threat of AMR. Professor Dame Sally Davies, the Chief Medical Officer for England and Chief Medical Advisor to the UK government, has emphasised that there are few public health issues of greater importance than AMR, both in the UK and across the globe. If unchecked, AMR is predicted to cause 300 million premature deaths worldwide, with a cost to the world economy of more than £60 trillion by 2050.

Historically, the majority of clinically useful antibiotics have been based on molecules isolated from natural sources. Even today around 70% of all the antibiotics that are prescribed are derived from so-called ‘natural products’; chemical compounds that are produced by microorganisms or plants to enable their survival in the environmental niches that they inhabit. Although natural product drug discovery was a mainstay of the pharmaceutical industry in the mid 20th century, the advent of structure-based approaches and combinatorial chemistry in the 1980s and 90s, led to industry migrating away from this approach. Now, some 20 years later, the emerging science of synthetic biology is enabling researchers to rapidly discover and optimise natural products for use as antibiotic leads, resulting in a renaissance in this important area of research.

Searching for answers in the deep

At the University of Bristol we are combining the innovations of synthetic biology with robotic environmental sampling to attempt to unblock the antibiotic discovery pipeline. If you want to find new and interesting natural products the best place to look is in microorganisms that have been exposed to evolutionary pressures that necessitate the acquisition of unusual metabolic innovations. The deep ocean is one of the most ‘extreme’ environments on Earth, and microorganisms that live there are considered to be excellent sources of novel natural products. We have been using a remotely operated vehicle, deployed from the James Cook research vessel, to recover environmental samples from previously unexplored regions of the Atlantic Ocean sea bed at depths  more than 4.5 km. Following sample recovery the bacteria present in these samples are grown in the lab and their capacity to produce new natural products with antimicrobial activity is determined. This project has only been running for 18 months but we have already isolated more than 1,000 previously uncharacterised microorganisms, and six new natural product-based antibiotic leads. This marine discovery programme is now being elaborated through collaboration with other researchers in Bristol and elsewhere to include microorganisms recovered from the Antarctic and from desert soils.

In related work, we are using molecular, genetic and chemical techniques to manipulate the cellular machineries responsible for the biosynthesis of antimicrobial natural products from marine bacteria. Building on previous work investigating the natural product abyssomicin C, from the bacterium V. maris, which was first isolated from the Pacific seabed, we are generating functionally optimised versions of this molecule that are better suited for use as antibiotics in animals and humans.

Strong research foundations

Our work forms part of a broad portfolio of research being undertaken at the University of Bristol focused on the discovery and development of new antibiotics. This builds on a strong foundation of EPSRC-funded interdisciplinary AMR research activity including the BrisSynBio Synthetic Biology Research Centre (funded by EPSRCand the Biotechnology and Biological Sciences Research Council), the EPSRC funded Synthetic biology Centre for Doctoral Training and the BristolBridge ‘bridging the gaps’ project, amongst others.

World Antibiotic Awareness Week, 13-19 November 2017: World Health Organisation

Twitter:  #AMRInsights #WAAW

Applying Social Science Theory to the Problem of AMR

By Claire Chandler, Associate Professor in Medical Anthropology, Co-Director, Antimicrobial Resistance Centre at London School of Hygiene and Tropical Medicine

Where did the idea for your research come from?

AMIS Programme Research Team during their inception meeting, at the London School of Hygiene & Tropical Medicine, July 2017.

AMIS Programme Research Team during their inception meeting, at the London School of Hygiene & Tropical Medicine, July 2017.

AMR is understood as both a biological and social problem. Often when we talk about the social side of AMR, we think of the ‘irrational’ use of antibiotics by patients and prescribers. From my previous research, we knew that applying this lens – and somewhat pejorative term – to the problem could have unintended consequences – such as holding patients responsible for decisions out of their hands. So I wanted to see how else we might think about AMR and the realm of ‘the social’. With colleagues Coll Hutchison and Eleanor Hutchinson, we reviewed existing social theory to see how this could be applied to the problem of AMR. As well as producing a report to help lay the land for others in this space, we worked with a group of collaborators to develop a programme of research to apply some of these theories in practise through empirical studies.

What is your research programme?

The research programme we’re working on is called Anti-Microbials In Society (AMIS), and consists of two empirical projects – AMIS Thailand and AMIS Uganda – as well as an online resource, the AMIS Hub, which is due to be launched on the 17th November 2017.

How did you set about getting the AMIS programme off the ground?

Firstly, we are fortunate to be working with excellent collaborators in both Thailand and Uganda. For example, our Thai co-investigators both completed their PhDs in anthropology on the use of antibiotics in communities in Thailand in the 1990s, and are now senior members of the Ministry of Health and Mahidol University. We will be able to compare the rich ethnographic work that they did back then with what they do now and to apply different theoretical lenses to that research. Our Ugandan team also have a strong background in medicines use studies. We also assembled a group of 18 inspirational mentors with expertise in AMR from across different disciplines. In July, we held a two-week inception meeting for our whole project team, with specific sessions for inputs from our mentors, as well as time to discuss social theory whilst walking across Regent’s Park!

What is the main aim of the research?

The AMIS programme aims to stimulate engagement with social research that presents different ways of conceiving, responding to, and framing AMR. In our empirical work, we want to be able to describe the rich social-material roles of antimicrobials in societies around the globe. We bring this together with research from other groups and individuals on our AMIS Hub website, where we provide simple summaries that offer policy-makers, scientists and funders new ways to conceptualise and act upon AMR.

Where does it fit into the AMR challenge?

Our use of antimicrobial drugs, including antibiotics, has escalated. Now a part of everyday life, we often are unaware of how much of the way we live our lives is dependent upon these medicines. We propose that the ways antibiotics are used is deeply embedded in the way our societies and economies work. It is important to understand the extent and nature of the way we have become intertwined with these medicines in order to understand the consequences of resistance and the best ways to reduce the threat of resistance. We want to ask new questions and generate innovative ways of thinking about AMR and tackling it, social science is very good at this!

How do you go about it?

In Thailand our research involves the mapping of antibiotic use, and the networks that antibiotics travel within, including in farms, factories, laboratories and during medical practise. The research will also follow antibiotics, microbes and discourses to national and international arenas. In Uganda we have three sites, seeking to understand how antimicrobials shape and enable ways of life within health care facilities, for urban workers and in different scales of chicken and pig farms in peri-urban and rural areas.

Our methodological approach promotes participant observation, in other words, immersion in everyday life, to better understand how antimicrobials are intertwined in societies and individual lives. We also seek inputs from a range of experts from different fields. For example, we are undertaking archival analyses on the history of antibiotics in different settings, with support from archivists such as Ross MacFarlane at the Wellcome Collection. We are also working with microbiologists and clinicians to map our findings together with theirs.

What does your day job look like?

I do a lot of organisation at the moment! We are preparing our protocols and documentary analyses at the moment, and will be starting pilot research in our field sites in January. When I’m in the field, I will be going along to clinics and sitting in and seeing how patients are being managed, talking with the health workers to understand their daily patterns and realities. Similarly, I will be spending time in urban slum areas, attempting to draw connections between the practises and constraints of everyday life, such as factory working or sex work, and the use of antimicrobials. I will be tuning in to how people talk about medicines, reporting the discourse around the reduction in their use and discovering alternatives that people might talk about.

All in all, we want to trace how people in different places and spaces relate to antibiotics and what roles antibiotics appear to be having in the fabric of everyday life.