Colistin? Colist-out

Antibacterial resistance is one of the biggest emerging threats to health across the globe, but the relationship between drug usage and growth of resistance is a delicate scale to balance. The use of therapeutic antimicrobial peptides (AMPs), for example, is met with concerns that we are running the risk of creating resistance to naturally occurring AMPs in the human immune system.

A recent study led by the University of Oxford’s Department of Biology seeks answers to this problem, and presents some striking results regarding the use of the antibiotic colistin in agriculture (1). I caught up with lead author Craig MacLean to find out what these results mean for the resistance crisis.

Watch the full, unabridged interview video above.

Before we talk about your recent study, could you introduce yourself?
 

I’m Craig MacLean, Professor of Evolution and Microbiology at the University of Oxford. I started my research career as an evolutionary biologist, trying to understand the kind of mechanics of evolution, how populations adapt by natural selection. 

A really cool example of adaptation by natural selection is antibiotic resistance. I started using that as a model to test evolutionary theory, but as I've worked on it more and more, I've become interested in resistance for its own sake and, effectively, in bacterial disease. That's what we work on in my lab – trying to understand what are the evolutionary drivers of antibiotic resistance. How can we use evolutionary thinking? How can we combat it? Why does it go away? Those are the main questions we tackle using a number of approaches.

In our experiments we challenge bacteria with antibiotics in controlled environments and watch how resistance evolves, trying to understand resistance in the real world. Sometimes we take samples from patients before and after they've been treated with antibiotics and use that to infer the processes driving resistance during infections. That's the experimental side, but we also do genomic work where we use bacterial genome sequences to help us understand resistance.

How did you get involved in the study? 
 

It was down to an antibiotic called colistin, which was discovered in the mid 20th century. It wasn’t really used in humans; it’s quite toxic and has side effects. However, it could be produced really cheaply and the side effects on animals weren't bad. In fact, researchers found that if you put it in the food of farm animals, it would be economically beneficial because they would fatten faster.

From there, colistin started to be used on a really big scale in agriculture. As resistance to other antibiotics increased, colistin emerged as an important last line of defense for treating infections in humans. I became interested because of this crazy situation where an antibiotic that was the last line of defense to treat serious infections in humans was the same one being used at a massive scale in agriculture, largely as a growth promoter.

The way colistin works is quite different from other antibiotics. It's a peptide; it has a chemical structure that's similar to the chemical structures of some of the compounds that our immune system uses to fight bacterial infections. And the way they attack bacteria is similar to how components of our immune system attack bacteria. In our case, it’s suggested that perhaps the resistance that eventually spread in agricultural settings is mediated by a gene called mcr-1.

Is the use of colistin limited to a few countries?
 

It’s mainly used as a growth promoter in Asia. The EU banned the use of antibiotics as growth promoters in 2006, and some other countries have followed suit. But at one point it was being used on a very big scale in China, which is where the best data comes from.

When the mcr-1 gene appeared, the Chinese government banned the use of colistin as a growth promoter. That’s another reason why I became interested in it – because we had samples that were taken before and after colistin usage, which is a good way to study the consequences of reducing use.

What were the overall findings of your study?
 

We found that the mcr-1 gene – which spread because of the use of colistin in agriculture – confers increased resistance to antimicrobial peptides from humans, but also from pigs and chickens. This is important because these are important reservoirs of colistin-resistant bacteria.

We found that colistin also increases resistance to some other components of the immune system. The gene actually makes bacteria more virulent toward moth larvae. Wax moth larvae – Galleria mellonella – are being increasingly used to study how virulent bacterial pathogens are. 

In short, the mass use of colistin in agriculture has driven the evolution of bacteria that are both more resistant to colistin and more resistant to some important components of our immune system.

What can we expect to happen as a result of using colistin in agriculture? 
 

That's kind of an open question. I think the good news is that when China imposed a hard ban on the use of colistin, consumption dropped by about 90 percent, which was followed by a reduction in the prevalence of colistin-resistant bacteria, both in agriculture and in humans.

So – reduce consumption, reduce the prevalence of resistance. It suggests that if we stop using this antibiotic, resistance will go down. The worry here is that antibiotic resistance is becoming a bigger and bigger problem. It kills somewhere between about 1.2 and 5 million people a year, and that number is increasing. One of the ways we need to deal with it is with new antimicrobials. There may be all kinds of peptides out there that are effective antimicrobials.

The colistin story warns us that if we're going to use antimicrobial peptides to treat human infections, we may end up driving the evolution of bacteria that are resistant not only to those peptides but to our own immune system. This is really important because our immune system provides us with an important first line of defense for fighting off bacterial infection.

How would you go about solving this issue?
 

People are excited about these peptides for good reasons. A journalist asked me, “Should we be banning the development of these as antimicrobials?” I said, “No, we're in a position where we desperately need new antimicrobials.” What we need to be doing is assessing – what are the risks in terms of resistance to our own immune system? So, we need to think about this carefully before we use any of these antimicrobial peptides.

Where does your research go from here?
 

That's a big question! We have three main ongoing projects in my lab. One is trying to understand what drives resistance during human infections. Another is developing new antibiotics, especially using phages – viruses that infect bacteria – as a potential alternative to antibiotics, and this is something that can complement antibiotics. The final line of research is trying to understand the mcr1 gene, how it is spread, how to stabilize it more. This has been a really interesting project and we'll be publishing a few more papers this year. It's like an onion – every layer we peel off, we find a new, interesting puzzle underneath.

We'll also be publishing some work showing that, initially, the resistance gene declined quickly when colistin use was banned because it's really costly to bacteria. So, if there's no colistin around, having this gene really harms them. But we've found that bacteria have evolved to offset that cost, which has helped to stabilize colistin resistance. So, it’s unclear even if this ban led to a big drop off in the prevalence of mcr-1, and it's unclear whether it's going to disappear or persist at a lower level.