ºÚÁϳԹÏ

The World Health Organisation calls it 'one of the biggest threats to global health, food security and development today.'

No matter who you are, how old you are, or where in the world you live – it's a threat to you. And the threat it poses is growing all the time.

It's making medical costs more expensive, taking up more hospital beds at a time when resources are tight, and – ultimately – killing people who might otherwise have been saved.

The name of this mortal danger? Antibiotic resistance.

This is spreading globally, making everything from pneumonia and tuberculosis, to blood and food poisoning, harder to treat.

Luckily, researchers and scientists around the world are stepping up to the challenge.

Professor Anastasia Callaghan is one of them. Anastasia is Professor of Biochemistry and Molecular Biophysics at the ºÚÁϳԹÏ.

She's a key player in an international, collaborative project to tackle antibiotic resistance by finding a way to shut it down for good.

How antibiotic resistance works

So, what is antibiotic resistance and how does it work?

To understand this, we first need to understand how bacteria and antibiotics work. Anastasia explains:

'There are good bacteria and bad bacteria. So, good bacteria in yoghurt keep your gut happy, and bad bacteria make you poorly – that could be anything from a chest infection to something deadly serious like cholera.

'You can't have modern medicine without antibiotics. For example, you can’t have surgery, because cutting someone open makes them vulnerable to infection. By fighting bad bacteria, antibiotics solve that problem. The same goes for the prophylactic antibiotics, which reinforce your immune system when it’s weakened by chemotherapy.'

In other words, when antibiotics stop being effective, we're all in big trouble.

But like all other forms of life, there is a strong selective pressure on bacteria. Put simply, this is the pressure to get stronger, to survive. When antibiotic drugs attack, instinct takes over and bacteria try to change – mutating their genomes to survive.

Bacteria are always dividing – that’s how they colonise parts of your body, to make you ill and spread to other people, too.

Take cholera. Once the bacteria are in your body, they switch on at a certain temperature. They then spread to colonise the gut. Once they reach a certain level, the bacteria release toxins that cause diarrhoea. That’s how some of the bacteria ‘escape’ back into the waterways, ready to infect the next person.

Imagine, at every stage, that the bacteria are communicating with one another – giving and acting on commands that take the infection to the next level.

You only need one bacteria that can resist an antibiotic. Because in the blink of an eye, it will become a whole colony. And it will keep spreading.

That’s how bacteria are beating antibiotics, and rendering them ineffective.

So, how can we fight back?

Traditionally, we’ve thought in terms of kill-or-be-killed. But rather than destroying the resistant bacteria, Anastasia and her colleagues aim to disarm them.

Finding the off switch

Anastasia seeks to understand the molecules that matter:

'If we can understand what molecules are switched on to turn bacteria into nasty bugs, then we can, essentially, switch those off. And therefore, those bugs are then not harmful to us.

'The idea is that your body would then just clear the bacteria, because they’re just inert – the scientific term is "attenuated" – and you don’t generate antibiotic resistance because you’re not trying to kill them.

'There’s no selective pressure on the bad bacteria to fight back. That’s the novelty of this approach.'

By reaching an understanding of the ‘switches’ that turn things on and off, it could be possible to control bad bacteria with new drugs designed to hit the off switch.

‘We’re looking at genetic information, to find out how we can turn a gene on and off.’

Stepping away from the metaphor, how does this actually work biologically?

Anastasia will tell you that DNA – the genetic code for life – makes RNA, which in turn makes protein – the building block of life. This genetic flow of information is essential to life.

Anastasia and her team are discovering that there’s lots of potential to exert control at the RNA level. Working with artificial RNA molecules, they are trying to modify and manipulate the process that determines whether or not they are made into protein.

If it proves possible to prevent nasty proteins, called toxins, from being made, we will have found the off switch. And drugs can then be developed to have that effect.

As you might expect from a project of such scope, this is a truly global endeavour. Anastasia and her colleagues work closely with researchers in the US, Brazil, and at Imperial College London.

Those collaborators have provided data and analysis of the molecules that are suspected to be important. Now, it’s a case of exploring different scenarios, to deepen understanding and develop models for different possible approaches.

Each team has its own particular area of expertise. Anastasia’s group have designed a unique technology for looking closely at molecules and their switches. By bringing lots of molecules together to be assessed in one go, this breakthrough will speed up the process of discovery. It’s a real step change in being able analyse the data and move forward.

All bacteria are different, so any future drugs resulting from this approach would need to be bespoke – developed specifically to hit the relevant off switch.

But there is still a common thread that would underpin all of this work. That’s why Anastasia and colleagues are currently looking at two very distinct pathogens, which will need to be manipulated in different ways. The first of these is cholera.

Outbreaks and breakthroughs

Cholera is not a pressing problem in Portsmouth. But massive outbreaks after natural disasters such as the 2010 Haiti earthquake (which triggered the funding for this particular strand of research) make cholera a very serious issue for the developing world. And it’s one that is on the frontline of bacteria’s war against antibiotics.

‘Cholera is one of the infections where you would really want this approach to work,’ Anastasia says, ‘because resistance is a nightmare.

‘Imagine an earthquake zone, with contaminated water, and lots of people go down with cholera. Giving drugs to lots of people at once is a great way to generate bacterial resistance.

‘So it’s much better to be able to give them a drug that means there can’t be issues with resistance developing.’

Because the genetic detail of different bacteria varies so much, treatments will have to be developed specifically for individual diseases.

But the nature of those future drugs would all be underpinned by the work Anastasia is doing – because it’s about establishing principles and ways of working, as well as tackling cholera in particular.

Although it will be time-consuming, there is an advantage to the need of developing targeted drugs. Anastasia explains:

‘The more we understand about the bacteria, the more we realise how unique they are. So medicines in some respects would have to be specific to that type of bacteria. But that is very nice because if you switch off a specific mechanism in a specific bug, you haven’t got other bacteria just randomly being affected and fighting back.’

In other words, as a by-product of this new approach to fighting infection, the resistance-generating side-effects of traditional drugs could also be eliminated.

Anastasia's other work

The other thread of Anastasia’s research focuses not on humans but pigs – though the impact on people is very clear.

With food security a strategic priority for the UK, Anastasia and her team have secured funding to apply her expertise in the name of animal welfare.

She and her colleagues are looking at a pathogen that affects pigs, spreading rapidly from one to another. It targets their respiratory systems and results in death.

Humans are not the only ones facing a problem with antibiotic resistance. Anastasia aims to identify how to switch off this bug in pigs before the infection can spread.

The implications, of course, go beyond the health and welfare of the pigs, to reach the stability of the agricultural economy, the food industry, and the wellbeing of both the farmers and the people who consume pork.

And, like cholera – and, indeed, all diseases – this is an infection which does not respect national boundaries. Every discovery that comes out of the labs in ºÚÁϳԹÏhas the potential to change lives for the better all around the world.

As Anastasia says, 'It’s important to be targeting global challenges.'

Microbiology, macro impact

Anastasia is proud that her research is playing a part in driving forward the UK’s efforts to eliminate the threat of antibiotic resistance. She recognises that it has exciting implications for the future of both the biomedicine and veterinary sectors.

What’s more, she’s thrilled by the discoveries, saying, ‘I like the excitement of being able to see chinks in the armour of bugs, and the novel ways they’re using switches.’

Most of all, she appreciates the difference she can help to make:

‘As a scientist, it’s the bigger picture that drives me. I want to find these things out because they can have that impact – better quality of life for people and animals.’

Anastasia has been fascinated by biology – and diseases in particular – since the age of about seven. She recalls being curious as a child about how bugs make us ill.

So it’s no surprise that, from her degree in Biology with Chemistry, to the microbiology slant of her PhD, through to her professional focus on biochemistry and molecular biophysics, her focus has ‘gone down to the nitty gritty molecules – smaller and smaller and smaller.’

But there’s no denying that the impact her research stands to make in the world has only become bigger and bigger and bigger.