New lasso-shaped antibiotic kills drug-resistant bacteria
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Nature.

Welcome back to The Nature Podcast. This week, a lasso-shaped molecule with antibiotic potential. And a huge study trying to settle a debate on how humans are impacting biodiversity. I'm Sharmini Bandel. And I'm Benjamin Thompson.

Antibiotics are wonder drugs that change the face of modern medicine. Without them, many of the procedures we take for granted would be impossible. But new antibiotics are desperately needed because rising resistance to the drugs we currently use is leading them to become less effective or, in some cases, completely ineffective.

For a long time, resistance wasn't such a pressing concern because new antibiotics and new classes of antibiotics were being found all the time, often produced by bacteria that live in the soil. But since the 1980s, the surging antibiotic discovery pipeline has dried up and slowed to just a few drips here and there. What's more, antibiotics essentially have a built-in timer for how long they remain useful.

Once resistance develops and starts to spread between bacteria, that timer begins to tick down. So the search for new molecules that could one day become drugs has become urgent. This week in Nature, a team described the discovery of one such molecule that shows promising antibiotic activity against a range of species. It's called larycydin and is a short chain of amino acids known as a peptide.

Specifically, it's a type of molecule called a lasso peptide. I called up Jerry Wright, one of the authors of the new paper, who told me more about the research and about lasso peptides, including how they got their name. So there are such remarkable structures. And instead of just being a linear series of amino acids with no shape,

What lasso peptides do is they fold back on themselves, and then there's an enzyme that forms another peptide bond amongst them so that it actually passes one part of the strand into the other, and it forms basically a knot. It forms a structure that looks like a lariat that we will remember from the cowboys from TV that have lassos. And that imparts lasso peptides with a very stable,

stable and distinct three-dimensional structure that has been used by nature many, many times over to develop these small peptides that have all sorts of biological functions. And some of them are antibiotics. And this Lariocidin that we discovered is the first lasso peptide that we know of that targets

the bacterial ribosome, which is a privileged target for antibiotics. There's a couple of dozen different antibiotics that target the ribosome, but we've never seen one of these kinds of peptides do so. And why is the ribosome such a privileged target for antibiotics to attack then? Yeah, so if you're thinking about where are the pressure points in a cell to be able to kill a cell,

you would say, well, the ribosome is the factory inside the cell that actually makes proteins and enzymes that are essential for all the functions of the cell. So if you can block that structure, then you are in the situation where the cells can't thrive and they can't live. And the story then of how you uncovered, found lariocidin is an interesting one. We know that huge amounts of antibiotics are made by soil bacteria. It's been a very rich place to look for them.

You've also done this, but you've done it over a very, very long time frame. Yeah. So in my lab, we started collecting bacteria and fungi from environments, mostly in Canada. And one of the postdocs in my lab thought that, like, what if we just wait a really long time and just wait for...

the organisms that otherwise would be hard to grow to grow in the lab. And so they went to my technician's backyard, got a sample of the dirt back there. There's nothing exciting about it. No offense to her, but it's just the backyard in Hamilton, Ontario.

and we isolated some bacteria and then put them underneath the bench for a year. And a year later, they opened up the box and they said, well, here we're going to find organisms that will take a long time and maybe there's going to be some unusual one. And one of those organisms that we cultivated from that experiment is an organism called pain of bacillus. It's just a

soil organism that was not uncommon, but it was an unusual one. And from that pain of bacillus is where we got lariocyte. So typically then, I guess, people work on the things that are easiest to grow in a petri dish. You've turned that on its head and said, let's look for the more subtle things, something that most labs who don't have a year to wait wouldn't necessarily investigate. Exactly. And I'm personally very impatient. And so I would not have done this experiment myself.

But the postdoc who did the work was, and the result was what we found. It was really quite a genius thing to do, I think. But this is kind of the beginning, I guess, of a detective story, right? You found this bacteria. You've shown that it makes something that in lab experiments can kill other bacteria. But I suppose you need to check that this isn't something that's previously known. You haven't just rediscovered something that already exists.

That's correct. And that's mission critical in antibiotic discovery. And it's one of the reasons why it's been so challenging to find new antibiotics, frankly, is because we keep finding the old ones over and over and over again. They're so successful in nature that they're very abundant and easy to find. And it actually turns out that this organism that we found, this pain of the cells, actually produces one of those old antibiotics.

But what we've started to do is take the mixture of compounds that are produced by these organisms and separate them using a process we call chromatography. And that helped us identify this new antibiotic that otherwise we never would have found. And so the next job then is showing what this molecule acts on. And you've shown that it works against the ribosome, which is, as you've said, one of the central things

to all cells really obviously we're talking about bacterial cells today now this is called a lasso peptide i have to ask does it work as a lasso is it sort of wrapping around the ribosome and sort of squeezing the life out of it oh that's a good question it doesn't the lasso actually gives the peptide a unique three-dimensional structure and what we found eventually it's binding to a site

on the ribosome that we call the A-site, where it fits in a very specific way that interferes with the proper translation of the message that is encoded from the DNA. And obviously bacteria are fantastic at getting around anything we throw at them, right? Antibiotic resistance is a thing. And there are plenty of antibiotics that do target the ribosome, but resistance to them is shoddy.

shown. So could bacteria just change the structure of their ribosome to avoid this LASU peptide? Yeah, it turns out that it's hard to do that because of where this LASU peptide actually binds. And it's very hard for the bacteria to change their ribosomes in a way that this lariocidin will not bind to it anymore.

I'd also point out we see absolutely no cross-resistance with any known mechanisms, including all the antibiotics that bind to the ribosome that we know of other than this one.

So it's hard to get resistance to this antibiotic. And there's no existing resistance out there other than, of course, the organism that makes it because it's resistant to it. And in your paper, you talk about testing this molecule against a variety of different bacteria, some pathogenic, of course, with a variety of success in different avenues. You know, one of the things that you like to see in an antibiotic is that it doesn't discriminate between bacteria, that it has what we would call a broad spectrum.

And it turns out that liriocidin indeed has that phenotype. It has activity against really important bacteria

so-called gram-positive pathogenic bacteria like Staphylococcus aureus and its resistant versions, MRSA or MRSA. It has activity against really important gram-negative pathogens, including one of the very challenging organisms called Acinetobacter baumannii. And it also has no toxic activity to human cells that we can see.

So that's very encouraging. And it showed some useful characteristics in experiments involving mice. That's correct. And so we were able to show that larrycidin actually has the ability to cure disease caused by one of these really challenging organisms, Acinetobacter baumannii again, in a mouse model of infection. So we were quite chuffed about it, to be perfectly frank. So you have this molecule then that shows promise against a

a variety of bacteria. What does this work not do? What are some of the questions left to answer about lariocidin? The discovery part, honestly, Ben, is the easy part. There's a lot of effort now that needs to go into tooling it into something that you could actually eventually see in human clinical trials. It's almost never the case that the organism that we found in the soil produces a molecule that will be the drug.

So what we're doing now is we are chemically modifying lariocyte and to try and improve its drug-like properties so that we can encourage

drug company somewhere to see some value in this and then take it further into the clinic. But of course, clinically, antibiotics do have limited lifespan. You talked about resistance being difficult to attain in the tests you did. But of course, resistance does exist because the bacteria that make it don't themselves die, as you've said.

So what is the long-term outlook for this molecule if it ultimately becomes a drug? What does it look like, do you think? In all candor, I think it's pretty good. The resistance mechanism that the producing pain to bacillus organism uses for self-resistance is

There's no good evidence that that will pick up and move and get into pathogens anytime soon. Resistance, of course, is always inevitable, but all the indicators so far are that this antibiotic does have some promise. And, you know, there's no such thing as a no-resistance antibiotic, but this might be a low-resistant antibiotic. Jerry Wright from McMaster University in Canada there.

To read his paper, look out for a link in the show notes. Coming up, a huge study of studies has been trying to tease out the exact impacts humans are having on biodiversity. Right now though, it's the Research Highlights with Dan Fox. A reduction in the amount of sulphur pollution emitted by ships has put clearer skies on the horizon, with less storm clouds and lightning seen in two of the world's busiest international shipping lanes.

Previous research has shown that pollution contributes to storm clouds and lightning along the heavily trafficked shipping lanes in the Indian Ocean and South China Sea. Now researchers have analyzed storm cloud and lightning trends in those areas before and after January 2020, the month that the amount of sulfur in ship fuel fell sevenfold in response to international regulations.

Their findings suggest that lightning decreased by 76% in the Indian Ocean and by 47% in the South China Sea between 2020 and 2023, with cloud water droplets showing a similar decline. Results the team say have fundamental implications for their understanding of aerosol-cloud interactions. Read that research in full in Atmospheric Chemistry and Physics.

Iguanas colonised Fiji after surviving an 8,000km sea voyage - the longest known oceanic migration by any land-dwelling vertebrate. Animals that can't fly or swim have a tough time reaching islands, but creatures have still managed to find their way to remote outposts by clinging to floating debris - a method called rafting.

Iguanas have rafted from mainland South America to the Galapagos, some 1,000 kilometers away. However, how these reptiles arrived in Fiji has been a mystery. To understand the origin of Fijian iguanas, researchers compared their DNA with that of iguanas in the Americas, finding their closest living relatives to be North American desert iguanas.

Genomic analysis suggests the lineages separated between 34 and 30 million years ago, right around when volcanic activity formed Fiji, and that timing implies that iguanas reached Fiji directly, rather than taking the slower route of hopping from landmass to landmass over millennia. Float over to the Proceedings of the National Academy of Sciences of the United States of America to read that research in full.

Next up on the show, reporter Nick Petridge-Howe has been looking into the effects humans are having on all the variety of life on planet Earth. When you think of the impacts that humans are having on the natural world, it won't come as much of a surprise that things like pollution, cutting down forests and climate change are largely negative. We find that the impact of humans on biodiversity, on the richness of

is negative that I think was somehow expected, right? It's sad, shocking to some level, but it was expected. This is Florian Altamatt, an ecologist who's been looking at this topic. But whilst the overall picture may not come as a surprise, how exactly these effects are playing out on biodiversity is less clear. This is where Florian comes in.

He's an author of a new meta-analysis published in Nature This Week. This analysis is a huge study that scours through the results of many thousands of other studies and he's been using this to bring together the combined knowledge of human impacts of biodiversity and to try and fill in some of the unknowns. For example, there has been debate amongst scientists about the nuances of how biodiversity has been impacted by human activity.

One question has been how similar or dissimilar communities of living things are becoming due to human influence. Something that can have important consequences for things like conservation and for the benefits animals, plants and living things provide to humans. By doing this meta-analysis, bringing everything together that is out there published, I think we can answer the question. Past studies have come up with conflicting answers to this.

with some saying that biodiversity is not really changing at local scales, and some saying the exact opposite. And Floen thinks that this discrepancy is because many studies have neglected to include good reference sites, in this case areas of the world that are not impacted by humans. These areas can help show how much humans are impacting biodiversity by giving researchers something to compare and contrast with.

But finding these reference sites is a bit of a challenge, given how much of an influence humans are having on the planet. In the end, the team had to comb through and discard many published studies that didn't do this. As Francois Keck, another one of the paper's authors, explains. We started with a pool of more than 70,000 studies.

And then we reduced this number to only extract the studies that are really relevant to our question. So we reduced that to more than 2,000 studies. So it's still a very large number. And we had to do that manually. So this was quite a big part of the work here. The final 2,133 studies covered 97,783 sites across the globe.

Each of them contained that vital reference condition too, either as a direct experiment where human impacts are trialed on one site versus one where they are not, or they had observational data on locations that were not impacted. With this done, the team could use statistical techniques to combine the results from these papers to look in very fine-scale detail at how humans are impacting biodiversity.

And the team's results show several things. As Florian mentioned at the start, they found that overall, human activity leads to a loss of richness, a reduction in the number of species present, perhaps to be expected. They also showed that humans make communities of organisms change, so different species will be present in the places humans have impacted.

But when it came to the subject of debate amongst researchers that I mentioned at the start, namely whether human activities lead communities of organisms to become more similar, also known as homogeneity, or more different, also known as heterogeneity, in this case, well, that was a bit more complicated. There is a diverging outcome when it comes to these communities being more or less homogenised. So it's not...

that human impact makes these communities always more homogeneous, can also make them more heterogeneous. And I think that is really the key finding that there it depends on the specificity of the system. So the team found it was all about context. When they looked at the data all together, it looked like there was only a small impact of humans on how similar biodiversity became.

But when you broke it down by different scales, say a tiny microhabitat of less than 10 metres, all the way up to continent-sized areas, then there were some differences. At the bigger scales, humans tended to make things more similar, whereas at the smaller scales, the opposite was true.

This study wasn't looking at exactly why this would happen, but one explanation could be that at larger scales, you tend to see more effects of humans moving animals around and introducing them into new places, so you may have more similar species overall. Whereas at smaller scales, you tend to get studies where researchers have used a very fine-toothed comb to look at what species are present or not, and so are more likely to find things or changes to biodiversity.

The analysis also allowed the team to look specifically at different impacts humans are having. So they could specifically look at the effects of pollution or climate change, for instance. Through doing this, they could show that pollution and habitat change were causing some of the biggest impacts on biodiversity, causing the most loss of species.

And whilst some of the effects were to be expected, there are big negative impacts of humans on biodiversity, the team were surprised at how much species that were present at any given location were changing in response to humans. What surprised me the most was the scale of the change, especially if we think about the composition of the community. So how some species replace others,

And I was expecting some change, obviously, but the scale was really massive. I think that was the most striking result. Whilst many of the effects shown in the meta-analysis were to be expected, whether this study settles the debate on how similar or dissimilar species are becoming due to humans remains to be seen.

One thing this study can't do, for instance, is to determine why exactly this is happening. It can only show there is a connection between human activities and changes to biodiversity. Altogether though, it paints a rather dire picture of how much damage humans are doing to biodiversity, with a general loss of species.

If biodiversity is something that we as a society want to protect and conserve, then we'll need to do better. And Florian hopes that this dataset could help here, as by giving such a detailed picture showing where and how large certain impacts are, it could help with planning where to focus conservation efforts in the future. We have very strong evidence on these pressures having negative effects. These are generally unwanted effects on biodiversity. So this is

One more very strong argument that stopping and reducing these pressures to halt and reverse biodiversity declines is needed. That was Florian Altamatt. You also heard from Francois Keck. They're both from the University of Zurich and the Swiss Federal Institute of Aquatic Science and Technology in Switzerland. For more on that story, check out the show notes for a link to their paper. Finally on the show, it's time for the briefing chat, where we discuss a couple of articles that have been highlighted in

in the Nature Briefing. Sharmini, why don't you go first this week? What have you been reading about? Yeah, so this is a really interesting article in Nature about some goings-on in Chile. And there's sort of a bit of a potential conflict between a bunch of telescopes, very big, very large, extremely large potentially, telescopes in the Atacama Desert in northern Chile, and this proposed green hydrogen energy complex.

that they want to build. Well, they seem like sort of two quite separate things. What's the conflict? It's a space issue, really. So you've got the Atacama Desert, right? And the European Southern Observatory has an observatory there and they're building several more sort of massive telescopes, lots of very exciting scientific potential. And the reason this desert is great for that is it's super dark...

So, obviously, if you're kind of looking at really faint distant stars, the darker the better. And the location of one of them, which is called the Very Large Telescope, is potentially one of the darkest spots. Right. And you kind of want to be away from people. You want to be away from light pollution. You want to be away from vibrations. So, desert is great for that. Desert is also quite windy and gets quite a lot of sun, which means...

Potentially great for solar panels and wind turbines. Hence this plan from this energy company to build this big complex where they can use solar and wind energy to get hydrogen from seawater. So green hydrogen. But this massive complex, it's going to have a port. It's going to have hydrogen production plants, ammonia production plants. It's going to have thousands of electricity generators inside.

and it's going to produce light and it's going to produce vibrations and the european southern observatory are currently saying this is going to be a massive problem for us right i mean as someone who lives in south london and always misses cool stuff in space oh did you see the meaties no all i could see was an orange glow did you see all the planets no all i could see was an orange glow you can see how this would be a potential issue so what's the state of play at the moment then well there's

Well, there's a bit of a confusion because the ESO have just released this analysis. You know, they're looking into what are the potential impacts of this complex. And from their point of view, it's looking very gloomy. So they've said that the existing Very Large Telescope light pollution would increase by at least 35%. And potentially at another site that they're building on the Cherenkov Telescope Array Observatory, light pollution could increase by 55%. So big

Big problem there. Atmospheric turbulence from the project also could cause vibrations that could damage the equipment. They're not optimistic about this. The phrase devastating irreversible damage, for example, their representative said at a media briefing, it will reach a point where it's highly likely that we won't be able to operate these telescopes. Right. But the energy company had already done analysis.

When they were pitching this, when they were basically saying, here's our plan, but we will comply with Chilean regulations, their analysis said, well, we think that the light pollution will increase by 0.27% at the Very Large Telescope and 0.45% at the Cherenkov Telescopic Array Observatory. So...

Their numbers are really different. And their reaction to this is basically like, oh, we don't know why these numbers are different. We're going to have to go and look into that. They said they're still working on gathering data from the ESO document, the European Southern Observatory document, to understand the discrepancies.

between the two sets of numbers, basically. So I guess then all sides are waiting on this new report before anything gets taken forward or more discussions are had? Yes, so there is a body that has to rule on that. So the Chilean Environmental Evaluation Service Agency basically have to make a call on whether this energy project can go ahead or not.

I get the sense that this wasn't necessarily predicted because the energy company and the European Southern Observatory had been working together to develop the plans for the array. So apparently they were talking about how the lighting design would work. The company sought their opinions on this.

But this isn't the only kind of opposition that the energy company have faced. There was already an objection from a regional governmental body from a nearby town, basically saying there's loads of problems with this, we should reject it and you should start again somewhere else. And from the European Southern Observatory's point of view, it is the location, again, that's the issue because it's remarkably close compared to a lot of other projects that are being built. It is quite close, within five kilometres of the Cherenkov Telescope Array. But of course...

It's thought that green hydrogen could play an important role in the energy usage of the future. And so getting sources of clean energy is something that humanity ultimately does need. Yeah. And, you know, I don't think any of these astronomers are opposing green energy production. So this particular project could...

save 1.5 million tonnes of carbon dioxide per year in terms of emissions. And then there's the local impacts. It's going to create around 5,000 jobs. There's lots of benefits for Chile's economic growth, for example. I think it is the location that is an issue and the astronomers are fighting very hard to protect what they've got, which is quite unique. The director general of the ESO noted that what we lose here cannot be replaced anywhere else in the world. Well,

Well, we will keep an eye on that one, I'm sure, to see how this knot gets unpicked. But let's leave the heat of the desert to a cool story that I've got this week. It's cool because it's in Antarctica and it's something that I read in Scientific American and it's looking at life at the extremes. Oh, I love that. That's just making me think of all the old David Attenborough BBC Nature documentaries where you go to a...

cold desert of snow and nothing and then it's like this little patch is actually filled with well what's it filled with? Well let's find out. So we're actually going beneath the waves here Sharmini. Now life is found throughout the oceans and seas of Earth right from the surface to you know the inky deep right at the very base but one place that's been kind of hard to know what's going on has suddenly become a

available and that's the sea floor beneath Antarctica's enormous floating frozen ice sheets. Oh so the sea floor under what would usually be completely covered by ice. Right very very hard place to get to as you might imagine and

It became easiest to get to because back in January, an iceberg the size of Chicago, I don't know exactly how big Chicago is, but I'm guessing pretty big, right? It actually broke off an ice shelf in the Bellinghausen Sea. Now, nearby were a team of researchers who were in a boat and they'd sailed to Antarctica to study the sea floor nearby and to look at the ecosystems and how they're impacted by climate change, that sort of thing, right? Yeah.

But then suddenly this event happens and they were like, let's go. Let's do this kind of thing. Because in the article it says this is like a very rare opportunity. It's a bit like turning a log over in a forest. I was just going to say when you lift up the wood and suddenly all the bugs are like, help.

But it turns out, in this case, the wood is an iceberg the size of Chicago. OK, so they went over there and they started researching this, one of these kind of opportune things. And they found a lot of life. And one of the researchers quoted in this article said there was a

surprised to see the amount of life that they did. And how does it compare to the bits of the seafloor they already knew about? Well, previous research looking kind of beneath the ice has involved things like drilling holes and putting a camera down in there, or looking at the area where an iceberg carved off, but quite a long time after the fact, right? So it's rare to get there

at the moment that it kind of happened. And they found loads of stuff, loads of new species. They sent a submarine down, this weird looking anemones, sea spiders, octopuses. And yeah, many of these are believed to be

to be new species. Obviously, it's going to require a lot of effort to actually work that out. But it's also thought that some of them could only be found here because Antarctica is kind of surrounded by this very particular current and it's described in the article as being like a moat around a castle. So it

It's going to take years to describe all of these species, but one in particular that stood out, and there's a picture of it which listeners, you should go and have a look at. We'll put a link to the article in the show notes. And it's a sea sponge that looks like kind of a vase, I guess. And the researchers estimate that it's potentially decades, maybe hundreds of years old, although analysis has yet to be done on it. So it seems like there's this thriving, diverse ecosystem of

under this really difficult to get to place that researchers haven't really had a good chance to look at before. I mean, lucky break for those researchers having the iceberg carve off right then and getting to describe a whole load of new species. So as with turning over a log, is it a problem that this iceberg just sort of left?

Well, that's a great question. And I guess that remains to be seen because this space underneath this ice sheet is such a kind of specialized ecosystem and animals do specialize to where they live. Suddenly taking the lid off like...

Well, it remains to be seen what happens. As I say, some of these previous studies have shown less diversity there. And ice sheets are retreating in Antarctica. And the future of this ecosystem, because of that, I suppose, is under threat. So I think this story shows that there is still an absolute wealth of animal diversity and ecosystems to be discovered. But as we heard in Nick's story...

Human activity is really impacting these. And so it's kind of a race against time to learn more about it while we still can. That's fascinating because you often hear about the bottom of the ocean being so vastly underexplored compared to sort of everywhere else on Earth. But I never really considered the fact that there's a lot of life under there that's just...

below ice and really hard to get to. 100%. So that's really interesting. Well, we'll put, as you said, links to both of these articles that we've talked about today in the show notes. You can go find them there. And we'll also put a link to where you can sign up to the Nature Briefing so you can get more of these kind of stories, but delivered to your email inbox. And that's all for this week. If you want to keep in touch, we're on X and Blue Sky, or you can send an email to podcast at nature.com. I'm Benjamin Thompson. And I'm Sharmilee Bundell. Thanks for listening.

♪♪♪

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