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Antibiotic resistance: How did we get here?

Non-antibiotic drugs may also have a role to play in promoting antibiotic resistance, Dr Typas says. Image credit - Dr Nassos Typas

Finding ways to enlist the bacteria living in our bodies to defend against infections while better understanding their role in promoting antibiotic resistance are key to fighting this growing problem, says Dr Nassos Typas, a microbiologist at the European Molecular Biology Laboratory in Heidelberg, Germany.

Antibiotic resistance is now regarded as one of the largest public health issues to face the world. In Europe alone, an estimated 33,000 people die every year due to infections caused by drug resistant bacteria. By 2050, it could lead to 10 million deaths a year worldwide.

While overuse of antibiotics is largely blamed for the crisis, Dr Typas, lead researcher of the uCARE project, says there may be other causes of antibiotic resistance that have so far escaped notice.

How important are antibiotics?

‘Alexander Fleming discovered penicillin in 1928, but it was not until the 1950s that antibiotics started to be used in a broad way. They have become one of the foundations of modern medicine, allowing us to perform invasive surgeries, transplantations, chemotherapy, care for premature infants and treat infections that used to lead to serious diseases and many deaths.

‘The impact has been transformative, as patients who get infectious diseases that used to claim many lives can now be given a course of antibiotics and be healthy again within a week or so.’

Antibiotic resistance tests; the bacteria in the culture on the left are sensitive to the antibiotics contained in the white paper discs. The bacteria on the right are resistant to most of the antibiotics. Image credit - Dr Graham Beards, licensed under CC BY-SA 4.0

What exactly is antibiotic resistance?

‘Microbes that would normally be inhibited by a specific antibiotic are able to grow in the presence of that antibiotic at concentrations we would give to patients in the clinic. So even when (people) take the antibiotic, the microbes grow just as if it isn’t there. Multi-antibiotic resistance is when (bacteria) are able to grow in the presence of several antibiotics.’

What problems does it cause for patients?

‘In a lot of patients who need fundamental medical care, it can be dangerous. For people who are critically ill, neonates, people coming out of surgery, if they have an infection that is multi-drug resistant and the first line antibiotics fail, there is a serious risk to their life. Then there are others who have long-lasting infections, which if they cannot be cleared (by antibiotics), there is a risk that they manifest as something more serious like sepsis, which can kill patients if they are not treated quickly.’

How do bacteria become resistant?

‘This was part of Fleming's inaugural talk about antibiotics – their very use would lead to resistance. By trying to inhibit the growth or kill a particular bug, you are putting a very strong selective pressure on it to develop resistance against the drug. Due to the population sizes, the speed with which bacteria grow and duplicate (and their genetic versatility) it is inevitable this will happen. Some drugs are easier for microbes to develop resistance to than others.

‘But eventually they will develop resistance to every single substance used against them.’

How is a microbe able to protect itself from an antibiotic?

‘There is a whole arsenal of ways microbes have to develop resistance, but very broadly they can modify the target the antibiotic acts upon, or they can modify the antibiotic itself by degrading it or altering it so it doesn’t work anymore. Then they can stop the antibiotic from getting into the bacterial cell in the first place by blocking its transport or pumping it out.’

‘We have a community of bacteria living in our bodies and they too can develop resistance to the antibiotics.'

Dr Nassos Typas, European Molecular Biology Laboratory, Heidelberg, Germany

What is causing it?

‘One of the causes is the broad use of antibiotics we have. In the last few decades, we have (increasingly) used them in a preventive manner in medicine and in food production and farming. The majority of the antibiotics we use today were developed between the 1950s and 1970s. There are very few classes of new antibiotics developed (which means that we are lacking drugs to treat microbes that have developed resistance to existing antibiotics).’

Are there areas where more research is needed?

‘It is still not very clear how much impact antibiotic use outside of medicine, like in farming and the food industry, are having on resistance. That could be studied much more closely.

‘We also don’t know much about the resistance of our (resident) microbial flora in our bodies and how they transfer this to pathogens.

‘Something new that we are looking at in the uCARE project is that other non-antibiotic drugs may also be promoting antibiotic resistance as a form of collateral damage. It could be an unnoticed factor in antibiotic resistance.’

Can you tell us more about that?

‘We saw a lot of non-antibiotics could inhibit the growth of gut microbes at the kind of concentrations that people take. We tested more than 800 non-antibiotics and one in four could inhibit the growth of microbes. The bacteria would eventually develop resistance to these drugs in ways that were similar to how they become resistant to antibiotics. It means that by taking these non-antibiotic drugs, we may also be driving resistance to antibiotics.’

Are there solutions to antibiotic resistance?

‘The one thing my group is exploring is how to use combinations of drugs. For most infections we currently use monotherapies, where just one drug is used, apart from one or two very specific infections like tuberculosis. With combinations of drugs the challenge faced by a microbe is far greater. These combinations also don’t just need to include antibiotics. They can be other types of bioactive compounds that can promote the activity of antibiotics.

‘There are efforts to find drugs that don’t inhibit the growth of bacteria, but rather block the development of resistance or its spread.

‘Another approach is to find drugs that are narrower-spectrum and target specific bacteria that cause an infection but don’t put pressure on the rest of the microbial community in your body (to develop resistance).’

Why is this important?

‘We have a community of bacteria living in our bodies and they too can develop resistance to the antibiotics we take and then pass this to pathogens. So, we are moving towards more targeted therapies that do not increase the number of microbes that can build resistance.’

Can we bring the bacteria in our bodies into the fight?

‘If we promote bacteria that control pathogens or remove them from our bodies, it could be possible. There are people trying to treat infections by giving patients cocktails of “good” microbes to fight off the pathogens and there are some clinical trials being done on this for Clostridium difficile infections, which can be quite antibiotic-resistant.

‘Another way people are approaching this is by using faecal transplants from one individual to another to change the community of microbes they have in the gut to defend against infections.’

Can we use other non-pharmaceutical approaches?

‘Another direction is phage therapy, where viruses that specifically infect bacteria can be used against pathogens. It is as old an idea as antibiotics but because antibiotics worked so well, it became largely obsolete. I think it is very promising that people are rethinking ways of using these.’

How close are some of these options?

‘I think we have quite a bit to go. No matter how much we do on administering drugs and surveillance, there is only so much progress we can make without new therapies. We need to think more smartly about therapy regimens to delay resistance, mitigate it and even reverse it.’

The research in this article was funded by the European Research Council. If you liked this article, please consider sharing it on social media.

This interview has been edited for length and clarity.

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