05/11/2018

These Bacteria Can Help Fight Antibiotic Resistance

17:13 minutes

Ten years ago, Dr. Gautam Dantas had one of those rare moments you hear about in science—a serendipitous discovery. He and his colleagues were trying to kill some bacteria they had collected from soil. So, naturally, they tried knocking them out with some antibiotics.

They were unsuccessful. The soil bacteria were resistant to the drugs—but the bacteria ate the very antibiotics that were meant to kill them. The discovery came as a shock to Gautam, now Professor of Pathology and Immunology at Washington University in St. Louis, and he says it changed the course of his career.

[The gig economy isn’t just for graphic designers and Uber drivers. Some scientists are forsaking academia—and not always by choice.]

He spent the next decade trying to understand the mechanism by which bacteria disarm and feed on antibiotics and how it might be used to combat antibiotic resistance in the environment. He joins Ira to discuss his latest work, published in the journal Nature Chemical Biology.


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Segment Guests

Gautam Dantas

Gautam Dantas is a professor of Pathology and Immunology at Washington University in St. Louis inSt. Louis, Missouri.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. 10 years ago, Dr. Gautam Dantas had one of those moments you hear about in science, a serendipitous discovery. He and his colleagues were trying to kill some bacteria they had collected from the soil. So naturally, they tried knocking them out with some antibiotics. Lo and behold, it did not work. Not only were these bacteria resistant to antibiotics, but the bacteria actually ate them like they were a snack. This was puzzling, mind blowing, even to those researchers. Why did they do this, and how did they do this?

Well, Dantas spent the next decade trying to answer these questions, as well as other questions about the antibiotic resistance in soil bacteria. And in his most recent research, he and his team finally cracked it. They were able to engineer a strain of E. coli to munch on penicillin. Here to tell us that story, as well as how bacteria-eating antibiotics could actually help with the fight against resistance, is Dr. Gautam Dantas, Professor of Pathology and Immunology, Washington University in St. Louis. Welcome to Science Friday.

GAUTAM DANTAS: Hi, Ira. It’s great to be on.

IRA FLATOW: It’s nice to have you. Now, this sounds like something out of a sci-fi movie. Aren’t antibiotics supposed to kill the bacteria?

GAUTAM DANTAS: Exactly. And as you said, 10 years ago, we were shocked by the finding. As you said, it was serendipitous. This is not what we were looking for. We were trying to look for bacteria in the soil that we’re degrading various other things. And honestly, we just set this up as a control, naively at that time, thinking, you know, what are compounds the bacteria couldn’t munch on? Well, clearly, antibiotics. And like with a lot of things with bacteria, we were wrong about them, because they’re just so much more amazing than we give them credit for.

And so–

IRA FLATOW: Yeah, go ahead. No, I didn’t mean to interrupt.

GAUTAM DANTAS: So we expanded the initial finding. We wrote a bunch of collaborators, and friends, and family to get soils from around the country, then went down the sigma catalog to get as many antibiotics as we could find, dunked them in these– those soils in the antibiotics, expecting to maybe find some trends, where some could be eaten and some couldn’t. And again here, fortunately we were wrong. Virtually every antibiotic we threw at these soil bugs, they could happily munch on.

IRA FLATOW: Wow.

GAUTAM DANTAS: And so that was the surprising finding.

IRA FLATOW: Our number, 844-724-8255. You can also tweet us at “scifri.”

Now, the thing about this is that these are not some kind of crazy, mutant, alien bacteria, right? These are just bacteria that live in the soil.

GAUTAM DANTAS: Absolutely. Yeah, we think these capacities that we’ve discovered are old and ancient, not something that anyone has engineered, not something that’s necessarily been selected recently. And also, the bacteria that we find are pretty diverse. So it’s not a particular specialist that’s figured out how to do this. There are lots of diverse type of bugs out there in the soil that, again, have this crazy capacity to use antibiotics the way we think most bugs using sugar to grow on.

IRA FLATOW: That’s amazing. How did you feel? I mean, did you feel like, there’s something wrong with our research, that this can’t be true, when you first discovered it?

GAUTAM DANTAS: Well, the first thing we did, you know, I think as good scientists is we were skeptical. So we first thought we’d done something wrong. So that’s why we repeated the experiment at scale. And then, of course, along the way, we started getting a little bit scared, because you know, again, we were taught that antibiotics are these sort of privileged molecules that allow us to kill bad bugs, which clearly they do. And here with these bugs who clearly didn’t care, [INAUDIBLE] almost laughing back at us.

And the other shocking part is that the concentrations that they were doing this at– these are concentrations of antibiotics that we used in these experiments are 50 to 100 times the amount that you would use to define resistance in the clinic.

IRA FLATOW: Wow.

GAUTAM DANTAS: And then these guys are just saying, ha! We don’t care. We’ll eat them. So we were shocked.

IRA FLATOW: Well of course, the obvious question is what bacteria you were working with, because could they make humans sick, if they escaped or get in– you know. They’re so powerful.

GAUTAM DANTAS: Right, yeah, great question. That was one of the first things we asked. We tried to identify what the bacteria were, tried to assess what risk they might pose to the clinic. Now, the bacterial that we looked at when we gazed into their genomes, if you will, when we look at who they might be, they don’t appear to be pathogens. But they’re very closely related to them. So their genus and species identities have close relatives that do cause diseases. But in this case, the specific bacteria that we isolated, we don’t necessarily expect those bugs themselves to be pathogens.

IRA FLATOW: So give me– we like to dive into the weeds sometimes, because a science program, we like to hear how it actually happened. So how are these bacteria able to eat the antibiotics? What’s their munching technique?

GAUTAM DANTAS: Sure, so this is the thing that took the 10 years to figure out, with a pretty big team of folks. And we kind had to throw the kitchen sink at them to really piece apart what they’re doing and how they’re doing it. And in the end, what we figured out was that these four bacteria that we focused on that could eat penicillin and a couple other penicillin type antibiotics could be divided into sort of three major steps.

The first step is inactivating the penicillin. And this is done using an enzyme called a beta-lactamase, that is identical to the enzyme that’s used by most pathogenic bacteria to be resistant to penicillin. So this is the first connection between this kind of weird property of eating the antibiotic to the more well known property of resisting it. So first there’s a resistance mechanism. And this kind of makes sense, because ultimately these bugs are still munching on a toxin. So the first step is detoxification.

The second step is then taking that penicillin molecule and kind of chopping it in half, sort of the head part and the tail part. And the reason I call it the head and the tail is the head part is the one that used to contain the structure that makes penicillin an antibiotic, the beta lactam structure. Turns out, that’s not the part that bugs care much about. It’s the other thing that remains. The compound is called phenylacetic acid. But that’s the part that then they’re going to munch on. So the second enzyme called Amadeus chops the penicillin to two, to give you the part that can be eaten.

And then, this was the kind of surprising and cool thing for us, which has allowed us to do the engineering you alluded to, was then, there’s a whole suite of enzymes– in this case a pathway– that can use phenylacetic acid and put it down into central metabolism. And the reason I said it was the kind of interesting and cool finding was when we looked at that pathway and then looked at the genomes of all bacteria that anyone else has submitted a public database, 13% of all bacteria that we looked at had this phenylacetic acid utilizing catabolon.

And so what that suggested to us was, you know, the downstream steps, the kind of difficult steps of converting this into the energy required to allow the bacteria to grow and to replicate exists in a lot of these organisms. And this is a shared strategy of using something that just happens to be part of the penicillin structure. And so those are the three basic steps, right. The inactivation, the cutting it in half, and then the catabolon.

IRA FLATOW: So now that you know how this works, how can you use this to combat the incredible amount of antibiotics we have in our natural system? Can you use these bacteria to go out there and sweep them up, or soak them up, or eat them, have lunch with them?

GAUTAM DANTAS: Yes, so there are two strategies that we think– that we discuss that could come directly out of a sort of application of this basic science work. The first is, indeed, a potential bioremediation, a clean up strategy. So we recognize that antibiotics, once they’re used in humans, or in agriculture, or even in the factories that make them, eventually some amount of that antibiotic will end up leaching out into the environment. And now that poses a contamination risk, because it could enrich full resistant bugs out there. So it’s possible that either the bugs that we have, or the E. coli that we engineered to also have this property, or even just the enzymes that we discovered, could be used as a way in which to decontaminate these antibiotics before they go into the environment. So that’s one potential application. Obviously if you were to do this in the genetically engineered fashion, in terms of the E. coli example, you’d have to have all of the regulatory things in place.

But then the second aspect, which is a little bit more tantalizing, because it kind of allows us to fight back at the bugs, if you will, is these enzymes that we discovered, that these bugs are using to eat antibiotics, ultimately are also giving us, now, building blocks of antibiotics. We’re breaking penicillin up into a bunch of substructures. And so, it’s possible that we could use these enzymes judiciously to pick those substructures and then stitch them back up, as a way in which to make chimeric antibiotics, new antibiotics. And so, sort of inadvertently, by studying how these weird bugs are eating antibiotics, we might actually have liberated new building blocks for the next generation of antibiotics.

IRA FLATOW: Wow, so where do you go from here with your work? What would be the next thing you want to know?

GAUTAM DANTAS: Yes, so a couple of things. One is, you know, we’ve showed this with penicillin and one other penicillin like antibiotic. But we know, obviously, there are many, many other classes of antibiotics. So there’s a little bit of a, sort of, rinse and repeat aspect to this, where we’d like to understand how bacteria that can eat other types of antibiotics, how did they do it? Maybe these are sort of generalizable strategies.

And then the second goes back to what I mentioned with the enzymes and the engineered bugs. Of course, we’d like to improve them. In our paper, the E. coli strain that we engineered to eat penicillin doesn’t do it terribly well. It would rather eat glucose if you gave it to it. And so we’d like to be able to engineer those enzymes, optimize that E. coli strain to get it to a stage where we could consider it a viable option for bioremediation.

IRA FLATOW: Isn’t there a danger if you have these really antibiotic resistant bacteria, what if you want– you need to kill the bacteria. What are you going to use to control the bacteria, should they get out of hand?

GAUTAM DANTAS: Yeah, that’s a great question. And that’s, again, why I mentioned upfront that anything you want to do with engineering, you need to have regulatory procedures in place. But the good news is even though these bugs can eat penicillin at this crazy high concentration, they are susceptible to a few other antibiotics. And so, even though they are highly drug resistant– so that was the other thing that we showed 10 years ago, which was scary. We tested all of these antibiotic eating bacteria against other antibiotics. I think we tested 18 antibiotics. And on average, they were resistant to 17 of them. So they are pretty multi-drug resistant, but there’s still a few vulnerabilities that remain. And so this is also why one thing that we might choose to do is rather than putting the natural bugs out there, you would engineer a strain that might have the penicillin eating capacity, but we make sure that it’s susceptible to a whole host of other antibiotics. If we need to kill it, we can.

IRA FLATOW: Interesting. Is this resistance that you found in the soil and the bacteria, is this something that humans created in the soil bacteria, or was it always naturally there?

GAUTAM DANTAS: So we think these eating capacities are ancient. And there’s really nice work done by others in the field, that we’ve also contributed to, to really, clearly establish that resistance to antibiotics is a natural and ancient phenomenon. There was this really cool paper by Gerry Wright and his group that went into the Canadian Beringian permafrost. And they cored out samples, so they could carbon date to be 30,000 years old. And then when they sequenced the DNA there, they showed they could find antibiotic resistance genes. So clearly establishing that resistance in the environment predates any anthropogenic– so, human– use.

What we’ve done as humans is not necessarily invented antibiotic resistance. It’s almost worse. There’s already this huge existing reservoir of resistance, and we, just by using antibiotics in the clinic and in agriculture, allowed that natural reservoir of resistance to get amplified. And so, that’s the scary aspect. Right? You don’t have to wait for this to de novo evolve. It’s already there. It can now transfer under selective regimes.

IRA FLATOW: Could you put the treatment– let’s say you take the enzymes that they’re making to kill the– to eat the antibiotics. Could you put those in, let’s say, wastewater treatment facilities, so as it comes out of the communities, it’s already getting taken out of the system.

GAUTAM DANTAS: That’s exactly one of the plans that we’ve discussed. So this is something where it gets around the genetically engineered organism risk, because they only work with enzymes, and they are going to transfer over. And much like any modern wastewater treatment plant– which is a bunch of stages, where you’ve got a settling phase, and they’ve got the degradation phase. In the future, you might imagine that there’s an additional tank, where you add on these enzymes that could break down the antibiotics. And now you’ve cleared out that contaminant from going out to wherever the wastewater goes.

And this is really important, because a lot of people have done studies– we published a paper a couple years ago looking at a wastewater treatment plant outside of Lima, Peru. And we used some methods to actually measure antibiotic concentrations in the influent. And the top 15 or 20 antibiotics that we used in Lima, we could detect in the influent. So we know that those antibiotics are certainly coming in through, at least in that case, the human wastewater treatment.

IRA FLATOW: I’m Ira Flatow. This is Science Friday from WNYC Studios, talking about this really interesting case of antibiotic eating bacteria, with Gautam Dantas of Washington University in St. Louis.

Could these bacteria pass along the ability to eat antibiotics to bacteria pathogens that could infect people? You know, isn’t it true that bacteria share their genomes, or they share their genetic material with each other?

GAUTAM DANTAS: Oh yes, absolutely. And so that’s been one of the major focus areas of our lab, is to understand the risk of this genetic transfer. But in terms of the actual eating bacteria donating these capacities to pathogens, I would say that the real risk is of the resistance gene. Right? That’s that very first step I mentioned, the inactivation capacity. Because that’s really the only thing that the pathogens are going to care about. When a pathogen is in the body, they’re not nutrient limited. They have lots of other food sources that they can munch on. So we just can’t speculate a reason why there would be any real benefit for a pathogen or a disease causing organism to get that eating capacity. But the risk certainly remains of the resistance enzyme of moving over. In fact, as I mentioned, that enzyme is exactly the same. So it’s already happened, effectively.

IRA FLATOW: I see. Let me see if I can get a quick phone call in from Elkhart, Indiana. Hi, Jessica, welcome.

JESSICA: Hello.

IRA FLATOW: Hi there, go ahead.

JESSICA: Thank you for having me. My question is about the necessary strength of this bacteria, such as in composting. Is the reason why they’re so strong to eat the antibiotics is because it’s a rotting fruit, and things in the soil? Like penicillin is made from the mold on an orange peel. So this would necessarily need to be strong enough to eat those substances.

IRA FLATOW: Good question.

GAUTAM DANTAS: Yeah, fantastic question, actually, because one of the things that we sometimes forget about with these compounds that we call antibiotics, because they’re so important, is in fact that almost every one of them are natural products. Right? There was this heyday of antibiotic discovery, between the ’40s and ’60s, really by people going out and finding bugs in the soil that could produce them. And so us finding this antibiotic eating capacity really kind of closes the loop and in the carbon cycle for bugs producing the antibiotics. And so then eventually, bugs evolved the ability to eat those carbon sources. So yeah, a fantastic question.

IRA FLATOW: Yeah, I mean, if the bugs are going to decay the food, you know, chomp on the rotting food that has natural penicillium mold growing in it, they have to be able to get past that, right?

GAUTAM DANTAS: That’s exactly right. And that’s been used as the argument to reconcile this finding of lots of resistance in the soil, that it made sense, right? These bugs have been there producing the antibiotics. So their neighbors must have resistance. They themselves must have resistance. Antibiotic eating bacteria are just one more part of that cycle, right. You know, they’re killing most of the competitors.

IRA FLATOW: Yeah.

GAUTAM DANTAS: Yeah, now this is a source that I can eat.

IRA FLATOW: I just have a few seconds left. I want to know how you were able to– did you have to grow bacteria in the lab? I know how hard it is to get it out of the soil to survive in the lab. Or did you not have to do that?

GAUTAM DANTAS: No, in this case, we did very much have to grow it. In fact, the way we were able to do it was by only providing the antibiotics as the sole source of carbon. And so then– you know, maybe there are a lot more of these guys out there that can do it, that are just hard to culture. So we just happened to catch the cultureable ones.

IRA FLATOW: Well, maybe you’ve discovered something people have been waiting to see, a technique. Good. Congratulations to you, Dr. Dantas. Gautam Dantas, Professor of Pathology and Immunology at Washington University in St. Louis.

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