Opinion Piece: Prof Mat Upton
Digging deeper for new antibiotics
The World Health Organisation describes antimicrobial resistance (AMR) as one of the greatest threats to human health, with the potential to undermine all of modern medical care. Not only are infections caused by resistant bacteria more difficult to treat, antibiotics are widely used to prevent infection during surgery, cancer chemotherapy and many other life-saving or -enhancing procedures. In some parts of the world, infection with resistant bacteria is now the leading cause of death in leukaemia patients; patients and their families are already having to make the devastating decision to go ahead with chemotherapy with the risk of developing an untreatable infection.
In light of the current global situation with the SARS-CoV-2 pandemic, AMR has been described as a ‘silent pandemic’ that warrants urgent attention and it was discussed at the recent G7 event in Cornwall, UK, following discussion at numerous previous national and international meetings (UN, WHO, World Bank, World Economic Forum).
The WHO and other organisations have recently reported on the weak ‘pipeline’ of new antibiotics being progressed towards clinical use. There are many reasons that there is not a plentiful supply of antibiotics and some of those are discussed here.
Use of antibiotics in any setting selects for bacteria that have randomly mutated to become immune to the action of the antibiotics. The genetically encoded mutations can be transferred to other bacteria rendering them resistant and mutations often confer resistance to more than one antibiotic.
Many of the more recently introduced antibiotics are modifications of previous ones, so resistance rapidly develops to most antibiotics as soon as they are used in the clinic as ‘tweaks’ of the currently circulating resistance mechanisms are selected for. To make genuine advances and have a significant impact, we need to find and develop new antibiotics that work in different ways to current antibiotics – those with novel mechanisms of action.
In the ‘Golden Age’ of discovery in the 1940s to 1960s, over 70% of clinically used antibiotics were discovered. They are all bacterial natural products (NPs) elicited by environmental microbes in their efforts to dominate their niches. NPs have been exploited in the development of modern antibiotics. NPs represent the most promising source of potential new antibiotics as we have barely scratched the surface of available diversity, but it has been suggested that the ‘low hanging fruits’ – todays current antibiotics – have been discovered already. Introduction of new technologies and databases has substantially enhanced the discovery process, potentially opening the door to new discoveries from the NP world.
Our work, based at the Derriford Research Facility at the University of Plymouth, aims to exploit NP diversity in the search for novel antibiotics that also have previously unexplored modes of action. I am currently UK lead for the South Africa – UK Antibiotic Accelerator (2020-2023), working with Prof Rosie Dorrington at Rhodes University to explore marine NPs. I also work with Professor Kerry Howell (University of Plymouth) to mine novel antimicrobials from deep sea sponges. By exploring marine environments that have not been searched for antimicrobials before, the groups aim to find new agents with novel mechanisms of action. A revolution in this respect is the ability to now access remote areas deep below the sea surface using remotely operated vehicles (ROVs) controlled by skilled pilots on research vessels. On almost each visit to the depths, Prof Howell sees animals new to science – I am interested in the bacteria that live in these animals and screen them for novel antibiotics.
Even with recent advances in technology to speed the discovery process and access to new environments to sample, antibiotic drug development has a further major hurdle to overcome. It has been suggested that the financial market is ‘broken’ for antibiotic development; now, it is very unlikely that the huge investments needed to cover R&D costs to get a new antibiotic to market (estimated to be $1billion) will be recovered through sales. There is a need to de-link profits from sales and several new models are being trialled where the value of an antibiotic is not just a reflection of how many doses are given. The true value of antibiotics in terms of human health benefits is immense, but difficult to quantify. Success with at least one of these new funding models will be essential if antibiotic drug discovery is to continue, protecting our modern medical care pathways and meeting the challenge of AMR.
New antibiotics and other novel therapies are critical to us tackling the evolving world of superbugs whilst constantly ensuring we work to preserve them. Understanding the complex barriers to antibiotic research and development must have an equal impact on how we value our stewardship efforts.
Pharmacists are one key stakeholder who can contribute towards the responsible use of these natural, life-saving and rare commodities which have been at the very core of modern medicine.
Images courtesy of the University of Plymouth & Marine Institute Ireland, Eurofleets 2
Professor Mat Upton
Mat Upton is Professor of medical microbiology at the University of Plymouth and Chief Scientific Officer at Amprologix, a company he established in 2018. Mat takes a One Health approach to addressing AMR. He is fascinated by naturally produced antibiotics and the majority of his research is devoted to discovery and development of novel antibiotic candidates.
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