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