Beating antibiotic resistance

I met Mat in his office in the new Derriford Research Facility building to talk about his work. At the top of his game and one of the new breed of medical research leaders working in the Faculty of Health, Mat is a microbiologist intent on developing novel ‘antimicrobials’ – antibiotics to you and me.

At school, Mat developed a real interest in biology and wanted to study the subject at degree level. Rather than study straight biology, Mat looked at biology related degrees and became inspired by what he read about microbes.

He wanted to study in a place near the sea and the hills and chose Newcastle University. Later, reckoning that a doctorate (PhD) and career in matters ecological might neatly satisfy his twin passions for matters watersport and ‘bugs’, he enrolled there for a PhD in microbial ecology.

A grant from Shell Agrochemicals and another from the government financed his project looking into bacteria that would attack other bacteria (so-called pathogens), which cause nasty commercial plant diseases such as tomato root rot. Although promising, the work did not reach the stage where his findings could be applied to develop a treatment, but it clearly shaped his direction of travel.

For the next 10 years he moved on through a number of university research appointments working in teams led by eminent scientists and always learning and developing new skills. Modest salaries and the uncertainty of multiple short-term tenures are something of a disincentive for anyone contemplating a career in university academia, but in Mat’s case there were other compensations.

Thank you for sparing the time to describe your work to the foundation and supporters of the schools. What is your role in the faculty? 

I am Professor of Medical Microbiology in the School of Biomedical Sciences and lead a team of research microbiologists; two post-doctoral research assistants, four PhD students and two placement students – one from Bath University and one from Austria. I am also Associate Head of School responsible for research strategy.

Sounds very busy. What are you researching?

We are looking for new antibiotics. Why? Well, to put it bluntly it is over 30 years ago since the last time a truly new antibiotic was introduced! 

We are rapidly running out of options to treat the ever more prevalent ‘resistant’ bacteria. 

For so long we have taken them for granted. But the first was only discovered in 1928 when a research assistant, Merlin Pryce, drew Alexander Fleming’s attention to the way that mould in a neglected culture was killing surrounding bacteria. Fleming published the findings. Later, Florey identified the active agent, penicillin, and we entered the age of antibiotics. 

Since then chemists and biologists have developed a succession of antibiotics, which until recently have served us well and saved countless lives. But nature never stands still and as new antibiotics are put to work strains of microbes that are resistant to them inevitably emerge – sometimes we see them even before the antibiotics are used clinically. All very clever on the part of microbes, but a big problem for us humans.

What approach are you taking to finding these new compounds?

Chemists, particularly those working for pharmaceutical companies, are very good at ‘tweaking’ the molecules of existing antibiotics until they find one that is more effective. Molecular biologists can manipulate the genetic code of bugs themselves. Fair enough, but all approaches have their limits and my reasoning is 'why not let Mother Nature do the leg work?' After all, that hidden world is a pretty brutal one and most of the antibiotics we use today were originally found being produced by environmental bacteria. Micro-organisms compete for space and resources and kill-or-be killed is the general rule. 

My belief is that there are sure to be bugs somewhere in this world which have developed substances poisonous to others and can be used against the bad guys; all my team and I have to do is to find them.

Sounds simple enough?

Not really. Let me give you an example. Staph aureus is important and widespread. It is normally harmless but if it gets into wounds it can be lethal – you will have heard of MRSA (Methicillin Resistant Staphylococcus aureus), the resistant bacterium causing so much trouble in healthcare facilities across the world. Whether it is the resistant variety or not, Staph aureus is found living happily on the skin of about 30 per cent of us and causes no problems. 

Working on the principle that there must be folk harbouring bacteria on their skin which have developed compounds lethal to fellow bugs such as MRSA, we set about collecting and culturing bacteria either directly from people’s skin, or indirectly from communal places such as surfaces that are often touched. We cultured hundreds, if not thousands of bacteria from such swabs looking for signs of a strain that was inhibiting or killing other bacteria. Painstaking, time-consuming work with lots of false leads and disappointments. But eventually…eureka! On the skin of a member of staff we found a bacteria that secreted something which seemed to kill off a range of other bacteria. We isolated the active compound; refined it, and named it ‘epidermicin’.

Terrific! How does it work? 

It punches holes in the ‘skin’ of a number of different bacteria. The bacterium – which is of course just a single cell organism – leaks out all its innards and dies. In terms of molecular dynamics, we do not know quite how the ‘antibiotic’ achieves this but we do know that it has a new mode of attack and a pretty neat trick I am sure you will agree.

Yes, indeed. Sounds pretty cool – maybe would make a good video game. But how do you isolate the active ingredient? According to my somewhat limited understanding, bugs live in a pea soup of chemicals. Must be like looking for a needle in a hay stack?

Chromatography, one of the great breakthroughs in science. The phenomenon was discovered by Mikhail Tsvet, an Italian of Russian descent, in 1903. It was subsequently understood and developed by two chemistry scientists Martin and Synge who, would you believe, worked at the Wool Industries Research Association in Leeds. They published their findings in 1941. Tsvet had discovered that if you stand a ‘stick’ of porous but inert material such as pottery in a solution of chemicals, the solution is drawn up into the column (try this with a sugar lump next time you have coffee or tea) rather in the manner of blotting paper. The brilliance was in noticing that the chemicals in the solution, separate out in the inert material of the column at different levels, according to how the molecules within the solution react with the substance of the column. 

Our column then ends up as something akin to a stick of rock that has layer upon layer of different ‘flavours’ along its length. In this way, the components of a solution separate out. Each layer can be painstakingly extracted from the column and tested, in our case for antibacterial activity, until the ‘active’ ingredient is identified. Of course the technique is much more sophisticated now, but that is the basic premise. Martin and Synge received the Nobel prize in 1951 for their work. Quite remarkable.

Work carried out in a wool research lab during the initial years of WW2 leading to a Nobel prize. Very British! But your approach sounds hugely labour intensive?

Well, it is, although we have amazing machines that will now process large volumes of ‘microbial soup’ in a matter of hours or sometimes minutes – but still using the same underlying principle.

Walking round the labs, one is struck by how much training must be necessary to use the equipment in a modern research laboratory.

Very true, and this is why a substantial body of PhD students is the bedrock of scientific research in any university. Setting aside the intellectual energy these bright youngsters bring to academia, learning lab techniques and how to use the equipment is a major objective for PhD students.

So, back to antibiotics; is epidermicin being produced now? 

Not quite, although we are a long way down the road. We know much about how effective it is against certain types of bacteria and it has unprecedented activity in an infection model, so we’re now able to enter the ‘pre-clinical evaluation’ stage. We know little about its toxicity, but will conduct some key experiments later this year and should it prove safe and effective could then enter human clinical trials and be on the market as early as 2023/4.

What other lines are you working on at the moment? 

Other strains of bacteria. During Antibiotic Awareness Week last year at the University one of us had the idea of inviting members of the public to collect samples around the campus using swabs. 

Believe it or not among them we found a bacteria secreting a compound of great interest, which needless to say we are evaluating at the moment.

And finally…Chinese pigs. What’s all that about?

This is a collaboration with Dr Michael Jarvis, also a member of the faculty. A group of us are developing a novel way of halting a deadly disease emerging in Asia. The bacterium, Streptococus suis, affects pigs and since China is the world’s biggest consumer of pork (it consumes 50 per cent of all pork), it is already a big problem for them. 

More alarmingly, it is now moving from pigs into humans where it causes serious infections of the nervous system – meningitis in particular. Michael has developed a revolutionary method of combating this bug and similar infections which arise in animals and then move on to infect humans. 

Thank you very much, Mat, that sounds like an intriguing topic for a future conversation. 

Thank you so much and the very best of luck to you in your important endeavours.