Season 3
Episode 4: Antibiotic Resistance – ft. Prof. Hinrich Schulenburg
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In this episode, Bea talks to Prof. Dr. Hinrich Schulenburg, a Max Planck fellow of the Max Planck Society and professor at the Christian-Albrechts University of Kiel (CAU), about antibiotics resistance. Prof. Schulenburg’s research focuses on the evolution of host-microbe interactions, as well as understanding the evolution of antibiotic resistance.
Antibiotic resistance happens when bacteria develop resistance against antibiotics designed to kill them. Antibiotic resistance has been developing globally, endangering the efficacy of antibiotics. Here, Hinrich gives a thorough introduction to antibiotic resistance. He defines what exactly antibiotics are, what they do, and why antibiotic-resistant bacteria are extremely dangerous. He explains the mechanisms via which antibiotic resistance arises, why resistance to antibiotics has become a worldwide epidemic, and, most importantly, what some ways that we might try to stop and maybe even reverse its spread are.
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Bea: Hello and welcome back to the Offspring magazine the Podcast, season 3! It’s Bea and I will be hosting today’s podcast. Today, we will be talking to Professor Hinrich Schulenburg who is a professor at Kiel University and leads a group at the Max Planck Institute for Evolutionary Biology. He studies the evolution of host and microbe interactions and, within that field, he is interested in understanding the evolution of antibiotic resistance. In today’s podcast, we will specifically talk to him about antibiotic resistance. What is antibiotic resistance? How does it work? What are the main causes? What are some solutions to the problem? And what are some of the discoveries that the Schulenburg lab has made? And we talk about much more. I hope you will enjoy this podcast!
B: Good morning, Professor Schulenburg! Thank you so much for being on the podcast today! So why don’t you start by introducing yourself?
Hinrich Schulenburg: Yeah, my name is Hinrich Schulenburg. I studied in Bielefeld and Cambridge university in the UK and then went back to Germany. And since 2008 I’m a Professor here, at Kiel University, in Northern Germany. And my research interests revolve around the evolution of host-microbe interactions. And within that field, I’m also very much interested in understanding the evolution of antibiotic resistance.
B: Yeah, great. So actually that’s the main reason, why I wanted to have you onto the podcast today, is just to talk about antibiotic resistance in specific. Because I do think that that’s a topic that’s very relatable. And a lot of people know what it is but I don’t know if everyone fully understands how it works. And that it’s such a huge problem also. So why don’t we start by trying to explain what antibiotic resistance is?
HS: I think we should start with what are antibiotics before talking about antibiotic resistance. Antibiotics are substances that either kill bacteria or inhibit their growth. And antibiotics can be found in nature: they are produced by microbes to compete with each other. There are other types of antibiotics that we have developed as humans: those are synthetic antibiotics. But at the same time, as I said, antibiotics are produced for millions of years by microbes in nature. This is important to keep in mind when talking about antibiotic resistance because, as a countermeasure to antibiotics, antibiotic resistance has also evolved early on. So this is part of the interaction among microbes when they compete for resources, that some then produce antibiotics and others, as a defence, evolved antibiotic resistance. So in a similar way, antibiotic resistance has also been around for millions of years. The use of antibiotics in medicine, in agriculture has, of course, led to an increase in selection for antibiotic resistance and, therefore, we do see an increase in antibiotic resistance among microbes nowadays. And there are different ways of how antibiotic resistance can be mediated and can work out. So there’s a variety of different mechanisms that has evolved over time.
B: So what are these different ways?
HS: These different mechanisms? So, on the one hand, antibiotics have specific targets. And mutations in the target structure can also lead them to resistance. So this is one way of how to defend yourself against these substances. Another quite common way that we find in bacteria are so-called efflux pumps – the basic and simple mechanism is whatever gets into the cell is immediately pumped out again. And this then includes these antibiotic substances. Yet another way of defending yourself is to produce enzymes that degrade or somehow modify the antibiotics and thereby inactivate them. So these are three common ways how bacteria can defend themselves against antibiotics.
B: And so why do these bacteria develop these pathways to defend themselves against the antibiotics? And how quickly also does this happen? Does it happen immediately as soon as they’ve been exposed once to the antibiotic? Or does this happen after multiple exposure?
HS: So I think we have to distinguish a little bit what happens now in those, sort of, human realm, and where we use antibiotics at very high concentrations in large quantities, and what has been going on in nature for millions of years. So, in general, these different mechanisms can evolve and they evolve because of very selective pressure due to the presence of these antibiotics in nature. And this selective pressure has increased massively with the use of antibiotics by humans: the use of antibiotics by humans in, sort of, a medical field, so for medical treatment, but also the use of antibiotics in agriculture. And antibiotic resistance can evolve extremely fast. So we may usually think, well, that it takes ages multiple exposures and so on, but in laboratory experiments, we can actually demonstrate that this happens within a day. It’s it is usually a question of how large the bacterial population is and how many mutations arise. It is also usually a question of how many genes in the genome may help the organism to defend itself, to obtain resistance. But there are a variety of these different mechanisms. There is a variety of genes that underlie resistance. And this can indeed happen extremely fast.
B: So just to clarify: you say, so this can happen even within one day? So that would be the antibiotic resistance that’s developed by one particular bacteria, for example, in your body or wherever? And so there’s that kind of antibiotic resistance but then there’s also, I guess, the resistance that happens when multiple bacteria develop antibiotic resistance, I think, because maybe it can spread, for example? Like one bacteria that develops antibiotic resistance could potentially spread, I guess, the same kind of genes to other bacteria, make these other bacteria antibiotic resistance? Does that also happen really quickly in like a day or is that slower?
HS: No, that also happens quite fast and that is also interesting. And also there’s a danger of making it too complicated. It is interesting when we look at fast evolution of antibiotic resistance, then I think it can usually happen by a let’s say three ways. One is that certain regions with antibiotic resistance genes become amplified in the genome. That is a mechanism that I think we usually now think is underlying faster evolution or can underlie fast evolution: that you have a certain region with favorable genes – you amplify it and then you automatically have more of the product. And this has been observed repeatedly as one mechanism where a single bacterial strain can evolve resistance very fast. So as one mechanism. Of course, we can also evolve resistance fast with point mutations, in a single bacterial strain, and here it is really dependent on how large the populations are, and how large the mutation rate is, and also how many potential genes could confer resistance against the antibiotic. On top of that, resistance can also spread by a horizontal gene transfer and I think this is what you may have been thinking of.
B: I mean the terminology I don’t know. I guess this is just me thinking about it in a non-biological way.
HS: And that is indeed also very interesting that, at least, when we explore the presence or the distribution of antibiotic resistance genes across bacterial genomes, then we often find these resistance genes on mobile elements, like plasmids, but also other mobile elements that are integrated into the genomes. So, suggesting that there is an advantage of having these resistant genes on mobilizable elements. And there are now numerous studies that have demonstrated that, if a population or a community of bacteria is exposed to antibiotics, then the resistance genes can spread fast with the help of horizontal gene transfer – so the transfer of these mobilizable genetic elements that then carry resistance genes. And that is indeed very fascinating, it’s indeed very fascinating to see that these mobile elements very often carry antibiotic resistance genes and are usually enriched for those antibiotic-resistant genes.
B: Okay, so now you’ve established the mechanisms, first of how antibiotic resistance happens, and then the second place is like how you can transfer it to other bacteria. So there’s different mechanisms of each. And do we see that certain mechanisms happen more often than others?
HS: A very good question. I would say we still lack more data on this. So the focus nowadays in bacterial communities is very often on horizontal gene transfer because that is, of course, also something very very fascinating. And in my personal opinion, it is a little bit neglected to also look at the importance of copy number variations or gene amplifications that I mentioned as one mechanism. And I think we also often neglect a little bit the importance of point mutations that arise very fast. I mean we see them, we report them but usually, when it comes to antibiotic resistance evolution, either in nature or in a clinical context, we look at these processes over longer time periods. But I’m convinced that this also happens very fast and this is something which is, yeah, somewhat understudied.
B: Yeah.
HS: So I wouldn’t dare to say what is more important. I think, as always, you can say it depends a little bit on the context. I’m personally convinced that all of these mechanisms do play a role and, yeah, and it indeed depends a little bit on the context.
B: Yeah, does it also depend on maybe what type of bacteria you’re dealing with?
HS: Definitely. So it’s interesting that these gene amplifications are quite well known and described, for example, for E. coli, and there it has been very well reported that these gene amplifications can really speed up the evolution of resistance. Whereas in some other bacteria, so we also work with Pseudomonas aeruginosa, a very important human opportunistic pathogen, and there are these gene amplifications at least seem to not play such an important role. So there are other mechanisms that are then speeding up resistance evolution.
B: Yeah, and do we think we’ve discovered, like, all the mechanisms possible? Or do you think that we’re still, lik,e at the beginning and we’re yet to discover a lot of new mechanisms I wish you can spread antibiotic resistance?
HS: I think we understand the basic principles, where I think we will still discover something new is regarding the details. So, for example, I mentioned horizontal gene transfer, so we have an understanding of how some of these mechanisms work that mediate horizontal gene transfer, but there are other mechanisms that are under debate or recently discovered, and where it’s not so clear how important they really are. And I could imagine there may be still others to be discovered. So it’s more a question of the details when we, I’m sure, we will discover more about the basic principles that gene amplifications, general mutations, and also horizontal gene transfer. These are the three main mechanisms that can contribute to fast resistance evolution. And now here I always emphasize evolution resistance evolution so depending on genetic changes or genetic mechanisms. There are, of course, other ways how bacteria can also defend themselves, at least transiently, physiologically so by changing part of the physiology. So this is a different way but, for me, as an evolutionary biologist, I’m particularly interested in those mechanisms that are genetically fixed and, therefore, really lead to evolution of resistance.
B: Yeah, so when we talk about antibiotic resistance, I actually think that I wanted to clarify this, because I think a really common misconception of the way people talk about antibiotic resistance is thinking that a person is antibiotic resistance but that’s not the case, right? It’s just it’s the bacteria or the pathogen that is antibiotic resistance and then a person acquires this bacteria and then the bacteria in them is just what brings the antibiotic resistance, am I right here?
HS: Yes, so it is the bacteria that evolve resistance and then a person either is infected with a bacterium that already has antibiotic resistance genes or expresses these genes, but it can also happen that you carry bacteria that then in your body evolve resistance. And this is also something that does happen quite often and it’s also a topic that is somewhat understudied. Because it’s usually believed that you get infected with something that is already resistant or multi-drug resistance, but this can also really happen in your body and it can happen quite fast.
B: Wait, can you explain that again I just need a bit more time…
HS: So let’s imagine that you have a bacterial infection and that is quite severe, and then your MD just prescribes antibiotics to you. So you take these antibiotics and then, while you take these antibiotics, you impose high selective pressure on these bacteria. And then you favor those variants that have mutations that confer resistance. And we have also performed one of these studies in cystic fibrosis patients that were infected with Pseudomonas aeruginosa and we could document that, indeed, resistance evolution can happen within two or three days during the antibiotic treatment. So these patients had susceptible populations towards the one of the antibiotics that they were treated with. So they had susceptible populations before the treatment started and then within two or three days they suddenly had a high prevalence of the resistant variants. So this can really happen in vivo, in your body within very few days.
B: Wow, I guess that’s extremely dangerous because then a patient might just, halfway along the treatment, be like, “oh, wait, no, it doesn’t work anymore”.
HS: Yeah, this is indeed one of the enormous challenges we nowadays face with a continuous spread of antibiotic resistance. And this has been emphasized by the World Health Organization already like almost a decade ago and during recent years. But with the corona pandemic, yeah, this got out of focus a little bit. But the threat is still there. So it is indeed believed that the enormous threat of antimicrobial resistance is one of the major threats to go global health. And it’s one of those top 10 killers of humans. And yeah, this is indeed extremely threatening or worrisome. And this is one of the reasons why researchers invested in trying to find new solutions to this particular problem.
B: Well, while we’re at this topic that it could become such a major issue, do you want to quickly explain why antibiotic resistance is such a big threat?
HS: Yeah, I think so antibiotic resistance becomes a threat because it could lead to treatment failure. So the more antibiotic or antimicrobial resistance spreads, the more we also have multi-drug resistance, the higher the likelihood that we become infected with pathogens that are resistant against all usable antibiotics, meaning we cannot treat the patients anymore, so we’re actually moving back into a situation before the introduction of antibiotics into medical treatment. So a situation where we thought that this would no longer happen or we would no longer be affected by this. And this is, of course, very worrisome because bacterial infections can kill people. I find this fascinating because, at least in the Western world, we are not really used to this idea because it usually never happens when we have a bacterial infection we can treat it. So nobody or very few people are killed by bacterial infections. This was very different before the introduction of antibiotics: bacterial infections were one of the major killers in human populations. And we thought we have solved that with the introduction of antibiotics but with the spread of antimicrobial resistance, and especially multi-drug resistance, we may be moving back into this, yeah, worrisome situation that we cannot treat these bacterial infections, so why does it happen? It happens because we use antibiotics, with the use of antibiotics we automatically impose selection on the bacteria, and we favor those variants that carry resistance. And this is, in my opinion, one of the important challenges today: to think of ways how we can actually still cure people that are infected but, at the same time, reduce selective pressure on the picture and, thereb,,y minimize the spread of antimicrobial resistance and especially multidrug resistance. And then that is, I think, a very important challenge recognized by the World Health Organization and where many colleagues are working on.
B: But an option would not be to just keep on developing new antibiotics and every year putting new antibiotics onto the market?
HS: This is something that is indeed followed by, or has been followed by, the World Health Organization, many national health organizations, and also many companies. In my opinion, that is a little bit short-sighted because the development of new drugs takes a lot of time, is very very expensive but, once you introduce them into medical treatment, you already know now that resistances will spread immediately as well. So this is one important lesson learned over the last 80 or 90 years, when we started using antibiotics that, whenever we introduce an antibiotic, resistance will emerge and evolve quite fast even for those antibiotics where it was proposed that antibiotic resistance cannot evolve. But bacteria are masters of evolution, they have a very high potential to evolve to any kind of new conditions. And, therefore, antibiotics are usually not a very big challenge for them. So this is important to keep in mind. So we can, of course, and I think it will remain an important strategy to develop new antibiotic or new antimicrobial substances. But, importantly, we should keep in mind that resistance will also always evolve. So just developing new drugs is not enough. And this is, in my opinion, one aspect that is currently also not ideal with the international and national health programs, regarding fighting antimicrobial resistance, that the major focus is on developing new drugs. I should add there’s another measure that is actually very important but this focus on only developing new drugs, without thinking of how we apply the drugs, is actually not sufficient. So we need to think, how we apply the drugs and there we can actually achieve much more than is currently done. I should quickly add, one other measure that is actually very important and that is proposed by international national health organizations, is to use less. You could argue that this is actually perhaps the most important measure of all. That we only use antibiotics when it is absolutely essential. So, meaning, when a person is infected with a life-threatening bacterial pathogen, then we should use antibiotics. Or when prophylactic administration of antibiotics is very very important for the survival of the patients, like after surgeries or things like that, or organ transplants. So in those cases, I would argue it’s essential and these are where antibiotics must be used. But in other instances, we could argue that antibiotics are actually not necessary. And there it would be very important to simply reduce the use of antibiotics in those cases.
B: Yeah, so I definitely want to talk to you about how we should be reducing or taking more care with how often we prescribe antibiotics. But I actually first wanted to go back to what you said, and you mentioned that there were some some people that thought that there were certain antibiotics that maybe bacteria wouldn’t be able to build antibiotic resistance to, can you expand more on that? Because I actually had never heard of that, and one of my questions was actually are there certain synthetic antibiotics where we see that bacteria build up resistance faster or slower to? So I think yeah, if you want to expand on that, yes?
HS: So, of course, when you introduce or develop a new antibiotic, it’s usually also a way of how do you sell the antibiotic, that you argue, “okay, resistance cannot evolve,” and then you do certain experiments in the lab and that may confirm it. The idea is, of course, that you try to develop antibiotics that target essential life functions of the bacteria, where you then think, “okay, mutations cannot really happen because the mutation would also compromise bacterial integrity”. And there were at least some antibiotics, where it was claimed initially that resistance either cannot or it will take really long time for the bacteria to evolve such resistances, but then reality has shown that the bacteria managed within a few years. And usually also this can be confirmed in laboratory experiments, where you vary the conditions, where you, for example, use larger population sizes, so more opportunities for bacteria to acquire the relevant mutations. So I think we simply have to accept it as effect, and that bacteria will always evolve resistance: they are really masters of evolution. There is, however, indeed the important point that it is sometimes easier for the bacteria to evolve resistance against certain antibiotics than against other antibiotics. And this indeed then has to do with how these antibiotics act. And also what are the diverse mechanisms for obtaining resistance, for acquiring resistance? So let’s imagine: you only have a single gene that would allow, or a single mechanism, that would allow you to become resistant against one particular antibiotic. And you compare it to another antibiotic, where you have like a hundred of genes that could confer resistance. So, of course, in the the latter case, resistance will evolve much, much faster.
B: Okay, yeah, that was that was interesting, I definitely did not know that.
HS: And I should add: so this is indeed also an interesting area of research that people try to understand, or try to identify, those antibiotics, where at least resistance evolution is constrained. So this is an important focus for sort of future antibiotics: to find those substance,s but also combinations of substances, where the evolution of resistance is at least constrained and, therefore, you know, will happen less often.
B: Okay, so there’s definitely antibiotics on the market, where antibiotic resistance just happens slower than others?
HS: Yeah, that is definitely the case. So like, for example, antibiotics that rely on peptide structures, there it seems that resistance evolution is slower. Because there it seems to be more challenging for the bacteria to acquire the the mutations that still ensure bacterial integrity, cellular integrity while also conferring resistance against the drug.
B: And do we actually really understand why it’s the case that, for example, peptide antibiotics allow evolution of antibiotic resistance to happen slower? Like, do we understand why that’s the case or was that discovered kind of by chance?
HS: No, this had been a focus also in the development of new antibiotics that tests are done, sort of, how likely it is that mutations can confer resistance. So it is part of the focus and to some extent we understand. So there is research going into this and trying to uncover the diversity of mutations that can lead to resistance against a certain drug. One should perhaps be careful because those studies are usually done in the labs, or they’re starting in the lab, and using certain strains of bacteria. And, of course, if you have the entire bacterial community with a lot of genetic diversity, there may be differences in the rate of resistance evolution, that we then only discover once the drug is actually used in medical treatment. But there is quite some research going into this, in understanding the likelihood of resistance emergence against different types of antibiotics.
B: You touched on this briefly actually previously and I kind of just want to talk about whether there are certain conditions that speed up the evolution of antibiotic resistance and what some of these conditions are? I think you mentioned this briefly before?
HS: Yeah, I mean, in general, it is using antibiotics. So whenever we use antibiotics we impose selection on the bacteria and then it is the question: where do we use antibiotics? So what is quite well known to everyone is that we use antibiotics in medical treatment but we also often overuse antibiotics in this area. There are strong suggestions how this should be reduced but if you look at the numbers this is not always happening. Let’s take one example. So if you have a cold, then many people go to their medical doctor and ask for an antibiotic. However most colds, not all, but most colds are caused by a virus against which antibiotics do not help. But many medical doctors prescribe these antibiotics anyway because they want to keep their patients. And because somehow these patients, they want these antibiotics. And they also may feel better afterwards but this may be simply placebo, a psychological event. So this is still happening, despite the strong recommendation to only use antibiotics where it’s really necessary. Then, there’s the case of prophylactic administration of antibiotics. And here you see actually a lot of variation among countries. So I’m still always shocked, is perhaps a little bit too dramatic, but surprised how often antibiotic antibiotics are prescribed in the US. So there’s a number published by a colleague that says that children at the age of 10, on average, have already seen 10 antibiotic treatments. And, of course, you can imagine, if you have been treated so often with antibiotics, then, of course, you favor the resistant variants in your body. And the question is: are these 10 treatments of antibiotics really, really necessary, when in other parts of the world this is not happening? Yet another example is that, in many countries, the prescription of antibiotics is very well regulated? So you need a medical doctor to prescribe these antibiotics but then, in other parts of the world, you can buy antibiotics in the supermarket. Meaning, whenever you do not feel well or whenever you feel like it, you just buy antibiotics and take them. And there you can count on it that it will often be used when it’s not appropriate. So with that uncontrolled availability of antibiotics, you also potentially at least favor the spread of resistant variants. So this is medical treatment. But on top of that, and this is often not very well known to everyone, antibiotics are also heavily used in agriculture. In fact, they are more used in agriculture than for medical treatment of humans. So the the numbers vary a little bit depending on the study, but of the overall use of antibiotics around 65% to 70% go into agriculture and only 30% to 35% into medical treatment. Why is this happening? This is happening for two or three reasons. One is that, of course, when sort of an animal husbandry in livestock, there is an infection, then you treat your your animals in order to to save your livestock and also to be able to continue to be productive. That is something that is also acceptable. Where it becomes more problematic is that it was found out quite early that a low dose of antibiotics actually enhances meat production. So antibiotics are actually used in animal farming for enhancing meat production a lot. And that is now actually prohibited in Europe and, as far as I know it, in the US, there are guidelines that this should not happen but they are not legally binding.
B: So it’s prohibited to use antibiotics on animals?
HS: No, it’s it’s prohibited to use antibiotics for enhanced meat production. So you can still use antibiotics in Europe to treat your livestock, if there is an infection, but you cannot just use it to enhance the, sort of, growth of the animals and meat production. So this is at least prohibited officially, but there are easy ways around it, because you only need to claim that you have an infection among your livestock. But in other countries, it is not prohibited at all and, as I said, so as far as I know, in the US, for example, there are guidelines that suggest it but it’s not legally binding. There’s a third point why antibiotic use in agriculture has increased and that is factory farming. So the more animals you have on limited space, and the more animals that are then also usually closely related, the higher the likelihood of bacterial infections. So if you have bacterial pathogen, then factory farming is like paradise. Because you infect one, and you have all the other animals that are usually closely related that you can then also affect, and they’re even close by. So it’s wonderful: you can just spread and infect everything. So factory farming is paradise for pathogens. And, of course, the more we do factory farming, the more we have to use an antibiotics to get rid of bacterial infections in the livestock. So this is a major problem where we are using antibiotics a lot. And again the more we use antibiotics, the more we impose selection on the bacteria and the more we favor the resistant variants.
B: Yeah, I mean, I guess also, for the spread of antibiotic resistant bacteria, that’s probably also just the perfect conditions are factory farming? Because the same way that pathogens can transfer over to other animals when they’re in closed space, so can antibiotic-resistant bacteria right? So I guess that through factory farming and by using so many antibiotics – that’s also how we we spread antibiotic-resistant bacteria so much?
HS: Well, one should add, so it’s usually argued that as long as we use different types of antibiotics in factory farming, or for for animal husbandry or livestock, than the antibiotics that we use for medical treatment, everything should be fine, so this is one argument. Another argument is that animals are usually infected by other kinds of pathogens, not necessarily the relevant human pathogens. But these arguments do not really hold because… so it is very well known that antibiotic resistance against one drug can cause cross-resistance against other drugs. This is very well described. So even if we use other kinds of antibiotics for farmed animals, the resistances that emerge there can still cause cross-resistance against the drugs that we’re using for medical treatment. The other argument that animals are usually infected by different types of pathogens, that is often true, but then also some of these pathogens can infect humans as well, and then become not really treatable. But the the larger problem is that we know that through horizontal gene transfer, the resistances that emerge in animal pathogens can jump or can be transferred to pathogens that infect humans. So the more we favor resistance in pathogens infecting animals, the higher the likelihood that these resistances will also spread to human pathogens.
B: Yeah, good, it’s really good that you clarified that point, because I actually just wanted to make that clear again to the listeners as well, that the reason why factory farming and the use of antibiotic in factory farming is such a danger is because then the antibiotic-resistant bacteria that they develop can then come to humans. I did not know that there was actually that argument that animals get infected by other pathogens that then would make it harder to spread to humans, but I guess that makes sense. But then my question would be: why don’t we use different antibiotics on animals that we aren’t using in humans? Because right now we use the same antibiotics on humans and animals.
HS: But this is this is a point I already made: so the the problem is cross-resistance.
B: Okay, yeah.
HS: So it is actually done in many countries. So I know, in Germany, there are certain antibiotics that are primarily used on animals. Interestingly these are then unfortunately sometimes the reserve antibiotics for human treatment. Which is then not so helpful in the end. But the the main problem really is cross-resistance and it’s a phenomenon that is very well described, so meaning: if you become resistance against one drug, you automatically also become resistant against other drugs. And this is now depending on the mechanism. So let’s imagine efflux pumps as one resistance mechanism that I briefly mentioned at the beginning. And efflux pump, they would not only move out all of the antibiotics that we have on the market but they can move out a certain range of antibiotics. So if an increased activity of an efflux pump evolved as a defense against one particular antibiotic drug, then this mechanism can also help the bacteria to be resistant against other antibiotic drugs. So meaning that these bacteria show cross resistance against these other drugs. And this then becomes the problem if, for example, there are resistances that evolved in animal pathogens against the drugs that are only used in animals, but if these bacteria then also show cross-resistance against the drugs used in humans then, of course, we have that problem.
B: Okay, I’m gonna ask another question and then you’re gonna see if I’ve understood the concept or not. So at the beginning, I asked you whether one of the solutions could also be to just develop more and more antibiotics year by year, but then, would that also not work because of cross resistance?
HS: That is indeed one of the potential problems at least. One always has to be careful with generalizations but many of the resistance mechanisms that are quite prevalent, at least have the possibility to generate cross-resistance as well.
B: Okay.
HS: So even if you developed a completely new drug, but the resistance mechanism that evolved against this drug, for example, if it is based on efflux pumps, which is a very common defense or resistance mechanism, then such increased expression and activity of efflux pumps can easily generate cross-resistance against other drugs. So so this would not save us from that necessarily.
B: Yeah. Okay, and so then going back to, also, the over prescription in humans, do you think that that was a bigger issue, let’s say, a decade ago and that it’s getting better now, or are we still at the point where we’re just like over prescribing way too much? And I know you mentioned that it’s obviously different in some countries and continents like in America. I think it’s also known that they just prescribe a lot more antibiotics than Europe, but if we just look at it in general sense?
HS: I would say it depends, as you already indicated, it depends on where you look. So I would argue in many countries, and I’m more familiar with the situation in Europe, there is a high awareness of the problem of antimicrobial resistance and there are now a lot of programs in place that try to reduce the use of antibiotics. So there is an awareness there, but the wrong use of antibiotics also still exists. So the example I gave regarding colds is something that is reality in Europe as well. It doesn’t happen all the time but it does happen. So in my experience and my opinion, in Europe, we use antibiotics less for medical treatment. In other parts of the world, I think the changes are not so severe yet. We also seem to use less in agriculture but clearly not as less as we actually should.
B: Yeah, and do you think that one of the main issues why we’re over prescribing so many drug antibiotics is because we don’t do enough testing to actually confirm that you have a bacteria in you? Do you think that’s one of the reasons?
HS: Yes and no. It is indeed so, let’s put it that way, if you have a patient with where you have the impression it’s a life-threatening infection and you have no idea what it is – you cannot wait for a diagnosis because diagnosis takes time. So in those cases, you would prescribe antibiotics immediately, you do not really have much of a choice. There are other instances where, for example, the infection is not so severe, where you could argue it would make sense to check first what it is and only then prescribe. And that could be done more. But it is also potentially more expensive because you then have to include a more detailed diagnosis of the causative agent. And that is the reason why it is often not done: because it simply then it becomes more expensive. So perhaps, to put it differently, by improving diagnosis, we could clearly then reduce the amount of needed antibiotics in medical treatment.
B: Okay, and would there be a possibility of developing, like, a rapid test? Like, kind of the COVID rapid test? Obviously, COVID is a virus, but could you also do that for bacterial infections?
HS: Yes. again, I’m a little bit careful because the challenge clearly is that often we also… I mean we have so many bacteria inside of us so just checking for a certain type of bacteria is not enough. And this is actually part of the challenge. But, on the other hand, you’re right: so there are ideas and developments where it is trying to use, for example, whole genome information. And different techniques show you can actually really fast-check for what kind of genomes are there for diagnosis and as help to be faster with knowing what the infectious agent really is. So let’s put it that way, there are investments and there is research going into that to improve diagnosis and make it much, much faster.
B: Okay, and so what do you think would be the best solution to try to reduce the number of antibiotics we prescribe?
HS: So first of all, I think we have to rethink, with that statement I may not make myself very popular in people doing agriculture, but I think we have to rethink how we do agriculture. And I mean factory farming simply is a problem for the overuse of antibiotics. But also using antibiotics for meat production is something we should simply not do. Then another point is that we also need to rethink when to use antibiotics in humans. So it really needs to be reduced to the absolute minimum. I think those are two important ways. So using less, I think, is the most important and the most efficient measure, irrespective of what kind of drugs we have. Using less, I think, will help us to yeah, to to tackle the antibiotic crisis, so the enormous spread of microbe resistance. The other part, and this is where I finally come in because I’m an evolutionary biologist, and I think we can actually use a better understanding of how bacteria evolve to also improve the way how we apply antibiotics. And this is something that is not done. What is even not done at all, but I know of colleagues from clinicians and so on, that are at least aware of that this is something they should consider. Because there are different ways of how we can apply antibiotics and not all of them lead to resistance fast. So there are certain ways of applying antibiotics that make it harder for the bacteria to adapt and evolve resistance. And if we have better knowledge about these particular treatments, treatment designs, that make it harder for the bacteria, then we can also apply the the antibiotics in an optimized way. And this is indeed something where especially evolutionary biologists try to bring in ideas, new ideas how treatment could be improved.
B: Okay, so that sounds really interesting. So why don’t we talk a little bit about your research now and maybe expand on what you’ve just alluded to in the different ways in which we can apply antibiotics?
HS: Yeah, so, again, the starting point is that the cause of the problem of antimicrobial resistance is that bacteria adapt. Bacteria evolve to the presence of antibiotics and they then evolve resistance. And if we now understand how they evolve and which selective pressures are important and also perhaps what kind of evolutionary constraints there may be, then we could use that knowledge to optimize therapy. To give or to start with one example: so using less is clearly one of the strategies which would minimize the spread of antimicrobial resistance – because you only impose selective pressure for a short period of time – and here it is, for example, interesting that, at least a decade ago and earlier, whenever you received an antibiotic treatment you were told to finish the package. So at least seven days or ten days – it depended a little bit on the country. And here, it is curious that the empirical evidence for this long period of applying it, or taking antibiotics, is that there was actually no very good evidence for that, that this is necessary.
B: What?
HS: So there are certain pathogens, where we know it is a “must” – because these bacteria hide in our body or replicate very slowly. So for tuberculosis infections, there is a “must” to take these antibiotics for very long. But there is now only recently increasing data that suggests a shorter time period of using antibiotics is as good as the long time period with respect to curing the patient. And it is clearly much better to reduce antibiotic resistance evolution. So the reason is that when we only take antibiotics, let’s say two to three days, for for an acute infection, then we keep the numbers low for a certain time period until our adaptive immune system kicks in and that usually can finish the rest. I mean we have a wonderful fascinating immune system that is highly effective. And we have so many infections normally and the immune system just deals with it, we don’t even notice. And with somewhat more severe infections, the immune system can also deal with it but it needs some time to become activated. With the antibiotics, we can simply support us for those days it takes until the adaptive immune system has been activated. So it is for certain antibiotics, there is now data suggesting that a treatment of two to three days is as good. And it is known that the shorter you expose the bacteria to antibiotics, the less likely it is that resistance really spreads. So this is one evolutionary insight that if you want that you can use. There are now other ideas that are also proposed and those ideas are currently researched and studied. Mainly in the lab so far but there are a few attempts where it is now also tried to transfer this knowledge to a clinical application. So one idea is based on evolutionary trade-offs. So in Evolutionary Biology, it is very well known that if you evolve a trait or if you adapt to a new condition, that adaptations may come at a price, because resources are limited or because of other genetic physiological constraints. So this is very well known, this has been known for for decades. It was relatively recently that something similar was also discovered and described in more detail in the context of antibiotic resistance. So there are certain types of antibiotic resistances that also come at a price. And the most fascinating price is that certain resistances cause increased susceptibility to other antibiotics. So again, so if you evolve resistance against antibiotic A you then automatically become more susceptible to an antibiotic B. So this is based on an evolutionary trade-off and this phenomenon has been termed collateral sensitivity. Because you evolve resistance against one drug that’s advantageous for the bacteria, but then the collateral damage for the bacteria is at least that they become more susceptible than they were before towards another antibiotic. And at first sight, this, of cours,e looks like a wonderful situation because it allows us to now exploit this evolutionary tradeoff and medical treatment by either combining two drugs that are associated with collateral sensitivity or by alternating these drugs one after the other. So it’s perhaps easier to understand if we alternate the drug: so we could in medical treatment first use drug A and if it then happens that the bacteria evolve resistance against this drug A, we know that we can then switch to drug B, against which the bacteria have become more susceptible, and that may help us not to kill off these bacteria. This is one realization with one phenomenon that has been discovered and described in more detail only comparatively recently. And there is now a lot of research going in this phenomenon, understanding really how it works, how widespread it is among bacteria, how often it really occurs, or whether there are sometimes that it doesn’t occur, and how well this can then be exploited for medical treatment. This, in my opinion, is a very exciting interesting research avenue and this is one idea that came from evolutionary thinking and that could help us to use the available drugs in a more effective way.
B: Sorry, so it’s called “collateral …”?
HS: Sensitivity.
B: Collateral sensitivity. So for the collateral sensitivity, is that then, so a treatment there would be to give multiple antibiotics?
HS: Yes.
B: One after the other? Or in combination?
HS: So both is possible. So there are studies, but again laboratory studies so far, using evolution experiments under controlled conditions that have demonstrated that, when this phenomenon occurs, then you can combine the respective drugs, so apply them simultaneously, and you would reduce resistance evolution. Or you can also apply them sequentially, one after the other, and it would also help to reduce the spread of resistance and also increase elimination of the bacteria. So this, under laboratory conditions, this seems to work very well. And now currently there are attempts by a variety of groups to transfer this knowledge into clinical treatment.
B: Okay, yeah, so that was my question, like, how much are we actually seeing this being used in practice? Or are these experiments just in the lab right now but haven’t been used in society yet?
HS: Yeah, so the majority of the work is in the lab but there are now attempts to transfer this knowledge into the clinic. And this is, of course, a little bit of challenge… Not only a little bit, this clearly is a challenge. So also in my personal case, so I’m an evolutionary biologist by training, so a basic researcher, and I’m not really familiar with all the requirements to start a clinical trial and so on. So we’ve teamed up with clinicians, also for the own ideas that we have proposed and developed. And that was for me an interesting reality check because it is not as easy as I thought to transfer this knowledge to treatment. And, of course, it makes sense: whatever works in the lab may not work in a similar way in reality because the human body is much more complex than the cultures that we have in the laboratory. But we have now developed strategies with our colleagues from the clinic, how we can now apply this knowledge into medical treatment. And this is ongoing, it’s something we are doing and I know that colleagues of ours are following similar approaches as well.
B: So if we go back to the collateral sensitivity, you mentioned so bacteria A, that’s the one you’re treating, and then that could make bacteria B more susceptible to antibiotic treatment?
HS: No, not that way. It’s the single, it’s the infecting bacteria that you try to move into an evolutionary dead end. So you target one particular bacterium that is causing an infection and causing problems. And you try to first use one drug to treat this bacteria. And then it may happen that this bacterium becomes eliminated, everything’s fine. But if this bacterium then evolves resistance against drug A, then if you have collateral sensitivity, this particular bacterium becomes more sensitive against the second antibiotic.
B: Okay, got it.
HS: This is then the antibiotic that you can then use in the next step.
B: Yeah, that makes sense. And my question here would be: how do you know then what drug B to use, what antibiotic B to use? Like can you predict how this pathogen will kind of evolve?
HS: That’s exactly one of the the foci of current research. So initially, this phenomenon had been described and everybody was very happy. But then, also came the realization that these collateral sensitivities may not always occur. So, for example, if you repeatedly treat the same bacterium with drug A, then, let’s say in 80% of the cases, collateral resistance evolves, but in the remaining 20% of the cases something else or it’s, at least, not collateral sensitivity. So one of the current challenges is to understand how robust this phenomenon is: so how repeatable it is and how easy it is to actually then use it for medical treatment. And at least the current data suggests the following: so there are certain type of pathogens and also certain type of antibiotics where collateral sensitivity does not always evolve. So when the bacteria become resistant against drug A, then sometimes they become more susceptible, more sensitive to drug B but in other cases not. This information is still usable but it requires improved diagnostics – so it would require that during an infection we actually monitor resistance evolution and also changes in susceptibility of the infecting pathogen. And then it can still be applied. But this also fits very nicely into the concept of precision medicine where we actually do try to tailor treatment to the specific context of the individual patient or a group of patients. So this is at least one of the findings at the moment. There are however also a few cases where the evolution of collateral sensitivity seems to be quite robust. So meaning that whenever you treat with this particular drug A, then you also very consistently get collateral sensitivity to a drug B. And this is, of course, one of the objectives of current research: to find these very robust cases. Because they could then potentially be always used without any further monitoring or improved diagnosis. But this is actually exactly ongoing research.
B: Okay, and so yeah, so tell me more about your research. I’m really interested! The things that so far you’ve described was really cool, are there other things that you study specifically in terms of bacterial evolution and antibiotic resistance?
HS: Yeah, so one concept that we are studying intensively next to collateral sensitivity is rapid changes between antibiotics. So the general idea is that we know that organisms in general can adapt easily to new constant conditions. And bacteria, as I said already repeatedly, they are masters of evolution: if you give them a new environment sooner or later they manage. Because we do find bacteria in under very extreme conditions, under very high temperatures, very low temperatures, under high radioactivity, etc. So if you just have one type of condition sooner or later the bacteria manage. But we do know that organisms usually have problems adapting to rapid unpredictable changes. So we know that organisms can also adapt easily if you have regular changes, so just take the seasons that we experience during the year. If you want dramatic temperature changes up to 50 degrees celsius, if you compare winter to summer. And we cope and organisms outside cope, they have evolved mechanisms how to deal with these enormous temperature changes. But it usually is much more difficult to adapt to something that changes really rapidly and ideally in a non-predictable way. And this is something we are exploring in the lab and we’re also trying to understand: which aspects make it difficult for organisms to cope with these rapidly changing environmental conditions? Our current results do indeed suggest that rapid changes between antibiotics make it much more difficult to the bacteria to adapt and evolve resistance. And we actually see a couple of different mechanisms that are important and that are relevant here. Actually, also including collateral sensitivity, is one aspect that can make it difficult. But the general idea is there. So if you change antibiotics comparatively fast, then bacteria have problems adapting to that. And here it is interesting that this is something that has usually not been done in medical treatment. So the current strategies that are followed is that you either use a single drug or you combine antibiotics. And what also has been done is to change antibiotics but usually, like, in a hospital after a month or six weeks or two months. And if you change antibiotics in such intervals, we also can demonstrate in the lab: that’s no big deal for the bacteria. So if you change antibiotics across longer, in the intervals, then they can still adapt. What we find in our experiments is that you need to change faster. Let’s say every 12 or 24 hours. Then you make it more challenging for the bacteria. And then, at least in our experiments in the lab, resistance evolution is significantly reduced. And this is one idea that we are currently proposing: that this could be also used as a strategy to optimize antibiotic therapy. And here we also teamed up with clinicians and now are exploring ways how this could be actually then incorporated into medical treatment.
B: And so a medical treatment, it would literally be like every 12 hours you take a different antibiotic?
HS: For example. So every 12 hours every 24 hours. And this is indeed something that we’re currently discussing with our clinical colleagues: how this can be properly implemented in, sort of, the real life context of a human body and a patient.
B: Yeah, yeah, because I guess no clinical trials have been done yet – this is all just still studied in the lab.
HS: So we have started with an observational study here. And here the results look promising. But the numbers are still so low that we cannot conclude anything yet. Therefore, also so far we cannot recommend it at all. But so this is something we have started and where we are exploring this strategy now, with our clinical clinics.
B: Yeah, yeah. I guess these are all solutions or potential solutions to solve the problem of antibiotic resistance in the future. Kind of that we talked before, how a lot of focus is on developing new antibiotics. But maybe it’s also the way that you administer antibiotics that’s important.
HS: So in my opinion, this is really essential. Sorry for interrupting. Because whenever we introduce new drugs, there will be resistance sooner or later. But if we consider or take advantage of evolutionary principles, then we can increase the the lifetime of the drugs that we are using. And I think this is very important. And it would clearly help us to optimize how we apply antibiotics to patients.
B: Yeah. Yeah, I guess here we still have the chance that, in upcoming years, you won’t be able to use these treatments anymore, right? Because like we said bacteria are masters of evolution so eventually they’ll catch up to our technology. But, I guess, there, we just have to stay optimistic that research is going to continue and find more and more solutions. And then, another, actually, thought that I had for talking about solutions: what about bacterial vaccines? Because usually now vaccines are used against viruses but can we also develop vaccines against bacteria?
HS: We can, and there are a couple of vaccines against bacteria already. It is interesting that most effective vaccines are targeted rather viruses. So it seems to be that it’s a little bit more difficult to develop effective vaccines against bacterial infections but they do exist. I must admit: it’s not really my field but I know that this is under development, and it exists, and this is clearly an alternative. So what we are proposing with using evolutionary principles to optimize how we apply the available antibiotics – this is one strategy. But there are other strategies out: vaccines is a strategy against bacterial pathogens, yet other strategies involve bacteriophages. So using viruses of bacteria that specifically infect bacteria, possibly even in combination with antibiotic,s to also make it more difficult for the bacteria first to survive but also to evolve resistances. So this is another strategy that is currently followed. That works well under laboratory conditions, at least in some experiments, and where there are also already first clinical trials, or at least attempts to trasfer this insight into medical treatment.
B: Okay, yeah. You don’t, by any chance, know why we’ve developed so many vaccines against viruses but not against bacteria? Like, what’s so hard about developing a vaccine against a bacteria?
HS: There, I simply have to say: it’s not really my field, I cannot really say. It’s an interesting observation that seems to have happened less. But I cannot really tell you why.
B: Okay, yeah, no, absolutely, no worries, so is there anything else maybe you want to mention about your research still?
HS: Perhaps, as a conclude sentence, that it is a great find to actually use basic research and apply to a quite relevant problem of a current concern. And I find it really exciting because it’s scientifically quite fulfilling. Because it’s fascinating to understand how evolution works, which factors contribute to fast adaptation versus slow adaptation. But at the same time be able to use that knowledge to, hopefully, contribute to new solutions to a really major problem for for human health. Yeah, that’s perhaps a nice concluding sentence.
B: Yeah, definitely. Yeah, so thank you so much for talking to us today! I learned a lot. And it was super super fun! So thank you so much for your time. And I wish you the best of luck also and I’m looking forward to seeing what kind of solutions you and your lab come up with.
HS: Thanks a lot it was a pleasure talking to you!
B: That’s it. Thank you all so much for listening! If you would like to learn more about professor Hinrich Schulenburg’s work, please visit the Max Planck Institute for Evolutionary Biology website or his website from the University of Kiel. And if you like our podcasts, make sure to follow us on our Twitter, LinkedIn, and Instagram page: this is the best way to stay up-to-date when a new episode is being released. Thanks again for listening bye!
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