New ways to combat the Antibiotic Apocalypse

0:16Hello, welcome to the Naked Scientist podcast. This is the programme that brings you the biggest breakthroughs and talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith and today as the world unites behind antibiotic awareness week we're exploring some of the exciting new scientific breakthroughs that we hope will help us to combat the rising tide of antimicrobial resistance.

0:46Antibicrobial resistance, or AMR as it's more frequently called, causes millions of deaths every year and it happens because the medicines we've traditionally used to treat infections are no longer working. With that in mind, global health bodies have come together each November in a bid to raise awareness about the issue. This year's campaign has just drawn to a close but despite these efforts new data from the UK Health Security Agency suggests that antibiotic resistant infections in England are continuing to rise steadily with hundreds and hundreds of new infections every week and the UK is no exception.

1:21This is a global problem that needs urgent global solutions and that's what we're going to explore this week. We'll hear shortly how scientists are taking novel approaches to combat the rising tide of resistance including a breakthrough vaccine approach for TB, ways to power up old antibiotics and a return to century-old technology based on bacteriophages. But first, how does antibiotic resistance happen and why? Colin Brown is an infectious diseases consultant with the UK Health Security Agency. Essentially, antibiotics, when used to kill bacteria, almost by nature, challenge those bacteria to find ways to become resistant.

2:04A lot of them are derived from things that fungus is produced to kill off bacteria. So penicillin, if we go back to the start, was produced by penicillium. And it was that fungus's activity to try and kill off bacteria that developed the concept of using these products for human use. But they've been exposed to them for millennia. And each time there's a product that tries to kill a bacteria, they are very clever and they find multiple ways to develop resistance. They can chuck the antibiotic out of the cells. Once they get into them, they can get their membrane to provide defenses so that the antibiotic never gets into the bacteria.

2:42They can have enzymes that break down the antibiotics. So there's a myriad of different ways that they can provide resistance. And we're giving many, many more antibiotics across the world. It means that we have to be now very, very careful about the use of antibiotics to ensure that they are appropriately targeted. to be given for the very right people at the right time for ideally the shortest duration as possible that will have a clinical effect so that we try and decrease that ability of the bacteria to develop resistance because we know that is happening more and more across the globe. Alexander Fleming who invented or discovered the effect that is penicillin he himself documented the emergence of resistance in his own experiments 100 plus years ago.

3:28So why has it taken all this time before now we're confronting this and we regard this as a big problem? I think if we go back historically, resistance was always known and it did develop. But there were ever more antibiotics that were available. There were different classes of antibiotics, So they worked in a completely different way. And those were appearing quite rapidly from early introduction of antibiotics in the late 40s and 50s, right the way through to the relatively modern era. We've seen a decrease in that. There's many reasons why that's the case. But we no longer operate in the understanding that we will always have a new antibiotic that will be just around the corner.

4:12And I think also increasingly we're realizing that some of the newer antibiotics, which by definition quite often target more and more bacteria, so they're more broad spectrum, we call them, but they can also have a wide range of effects on the things and the bacteria that live with us very happily and kind of live alongside us in our daily lives. So I think we're also recognizing the tension and the difficulties of giving lots and lots of antimicrobial prescriptions. And I think an increasing global recognition that in lots of the world, particularly where there is challenges with access to medical diagnostic tests, so they don't really know what bacteria specifically they're able to treat and therefore a rather blind use of antibiotics, that resistance is really, really becoming a big, big problem.

4:58And if it happens globally, it happens everywhere because people travel, bring bacteria with them on their skin, in their guts. And therefore, if something is happening in one part of the world, it will soon happen in many parts of the world. Usually, if there is a demand for something, then an economist would tell you a market will spring up to serve that demand. So why is there a huge demand for novel antibiotics and an empty pipeline? There is a paradox to the financial benefits of developing new antibiotics. If you have a new cancer drug or a new heart drug and those prove to be very beneficial, you want to give that to as many people as possible to create the best impact.

5:47because of the resistance issue and the fact that a new antibiotic say a new class of antibiotic completely different than others before and then maybe one that's going to be effective against the most resistant infection so from our perspective the most valuable new class of antibiotic we want to lock that away and put it in a box and only release it where there are no other options because there is likelihood of the more we use that the more resistance to be developed. So we want to protect that for as long as possible because it is a last resort antibiotic. That creates a real disincentive for manufacturers to invest in that.

6:27Now we have tried to create novel ways in the UK. We have a subscription scheme pioneered by NICE, our National Institute of Clinical Excellence and the NHS in England, whereby we are giving a bulk purchase cost for novel antibiotics. So even if we only used it once or twice or a handful of times, we will give manufacturer a promise of a multi-million pound investment year on year for up to 15 years to try and incentivize people to bring novel drugs into the system. But even with the UK on its own is a relatively small market. European countries are thinking of other ways to do something similar as are Canada, Australia, Japan and the US.

7:10But those market incentives haven't yet coalesced into something that is really going to change completely the way that companies currently see the investment potential for future antimicrobials and antibiotics. And therefore we anticipate this problem will be with us for a while. So we've got to think laterally. We've got to think originally about other solutions. So what might they look like? Is it just down to better use of antibiotics? if the more we use one of these agents, the more we get resistance? Is the answer just to try to use less? There is a degree to which we can use less. We call it stewardship.

7:47We steward the use of antibiotics, and we're trying to reduce the use of inappropriate antibiotics. But people are getting older. They're getting more infections. They are living longer with complex diseases. We have more people on immunosuppressive treatment that lowers their immunity to infection. So we will be giving more antibiotics. we know these resistances are going to increase so though we can try and create better stewardship we also need different approaches and some of those different approaches are what we are going to hear about next thanks very much to colin brown from the uk health security agency now one place that scientists are searching for novel antibiotic strategies is within the medicine chest that we already have because sometimes we can find powerful new drugs lurking upstream as intermediate products in the manufacturing process that produces the chemicals we already have.

8:40And sometimes that manufacturing process is actually inside a microorganism itself. This was exemplified recently when British and Australian scientists were studying an antibiotic molecule that we've known about for many decades, which is called methylinomycin A, which is made in a series of chemical steps by the soil bacterium Streptomyces. What Warwick University's Lona Alkalaf and her colleagues did was to block one part of the pathway making that molecule in the bacteria and then isolate the chemicals that accumulated upstream. One molecule they collected turned out to be a hundred times more powerful at killing certain classes of bacteria and despite considerable effort the team were unable to make their test microbes become resistant to it.

9:26If you were to go outside and scoop up some soil you'd find a whole bunch of bacteria in there and they would be making all kinds of antibiotics to try and kill each other in the soil. And so what we do in our research lab is we try and find new chemicals that might have antibiotic activity, but we also try and work out how they're made. So how does the bacteria assemble these complex chemicals? And there's one particular compound, which is called methylomycin, which is produced by a bacteria that lives in the soil. And we were essentially trying to work out how that's made. Presumably the motivation for this is that the world is running short of antibiotic compounds that still work in the face of rising antibiotic resistance.

10:0610 million people per year by 2050 will be dying of bacterial infections that we just don't have any antibiotics to treat and so we really need new antibiotics and we need new versions of the antibiotics that we've currently got and many of the antibiotics treat these infections have come from bacterial sources it's something like 80 % and we think the best place to look for the new ones is where you found the old ones. Tell us about the compound you were looking at then because that's not new is it? That's one that we've known about I think it was documented in the 60s wasn't it? Methylenomycin A which is your starting molecule.

10:40So why were you looking at that one in particular? Because it could be made in an interesting way so we're also interested in the enzymes so these are proteins that speed up the reactions that we need to get to the final product. Some of those of interest in chemistry and we're actually more interested in what that chemistry is and how we get to the natural product for the purpose of using that to look at other systems in other bacteria. Oh right so almost like the production line that the microbes use to make this stuff you're interested in unpicking that not because it will necessarily make something like that molecule but it might make other exciting molecules that might be useful to you.

11:14Yes it might make other exciting molecules or we might be able to pick apart the different steps of that assembly line in order to put it together in a different way say to make a different compound that might have antibiotic activity there's lots of reasons to understand the fundamental ways in which these chemicals get made by the bacteria and what emerged when you began to to do this unpicking of the production line what surfaced say there's five steps along the pathway if you inactivate the ability of the bacteria to do that last step essentially you get intermediates blocked up in the same way say a car assembly line if you don't add the paint you end up with lots of cars that are just silver because they're not painted so in our case that box up intermediate is another chemical with just a slightly different structure and what's interesting is the phd student who was working on this project just took it upon himself to be like oh just i'll just check if this has any antibiotic activity it's not something we normally do when we make these intermediates but he thought he'd just check it and when he checked it he realized that it's actually a hundred times more active than the final product that the bacteria intends to make.

12:19That begs the question then, well why didn't the bacteria use it themselves? Why did they chew it up and turn it into a new chemical that's a weaker antibiotic? It's a very good question. The fundamental answer is we're not sure. It's possible, one, that the bacteria is not using it as an antibiotic in the first place because it is an antibiotic and that's what we assume the bacteria is making it for. It could be using it for regulation or to communicate with other bacteria or a variety of other reasons. It could be about which types of bacteria it's active against. So it's possible that our intermediate just happens to be active against something that we really care about treating, but the bacteria in the soil is not so bothered about killing that because it never encounters it.

12:58It could just be a quirk of evolution where this particular strain already had another antibiotic that it was making and that one was playing a certain role and so there's no point expending all that energy and making two different products. So it developed this one to do something else. It's all a bit of a black box. We don't really know why they're making what they're making in lots of cases. How did it get tested though when it emerged that it might have this interesting antibiotic property? How did you then take that forward and test it and against what? So we've tested it against a number of different bacteria.

13:29Bacteria typically split into two different types. You have gram positive and gram negative. Gram positive is the one that ours works against. It is common that you get antibiotics that are only active against that type because the gram negatives have a different cell wall that can be quite hard to penetrate. And the second thing is take some of those strains and try to induce resistance. So if you take vancomycin, which is one of the clinically antibiotics, which there is a lot of resistance to, if you take one of those strains and you can make those strains resistant to vancomycin very easily.

14:00And if we try and do that same approach with our new compound, it seems to be much harder to do for our compound to get resistance. And are the strains of microbe that you're testing it against, are they clinically relevant? Are they the kind of thing that would crop up in the clinic and are a real headache for hospitals and infections? We use lab versions of those strains just to get an initial indicator of the kind of bioactivity that we can see. What's your plan then? Is it that you're going to investigate the compound itself to see, well, could we repurpose this into a really potent novel antibiotic?

14:33Or are you going to say, well, let's work out how it works and then see if we can build something like it or both? I think both essentially the first step towards the kind of clinical development side is we haven't yet tested it for human toxicity so that's obviously a really important aspect of drug development so probably the first step there is to see how it interacts with human cells and what selectivity we get and then whether or not that is a problem we're also really interested in what the target of this new drug is because we don't really know we think it's something to do with the cell wall but we're not really sure and once we know that target we can then think about can we develop similar structures that might be more active or more selective the various kind of hurdles you have to get over before you can reach clinical trials.

15:17Lona Alkaff at the University of Warwick on how we can delve into the production chain for existing antimicrobial compounds to discover ways to make new ones. The Naked Scientist podcast is produced in association with Spitfire Cost-effective voice, internet and IP engineering services for UK businesses. Find out how Spitfire can empower your company at spitfire.co.uk.

15:44Music in the programme is sponsored by Epidemic Sound. Perfect music for audio and video productions. This is the Naked Scientist podcast with me, Chris Smith. And today we're examining the future of antibiotics and new avenues that scientists are exploring to conquer the problem of antimicrobial resistance. In a moment, a new way to prevent something that is a massive antibiotic headache, and that is TB infection. But first, on the subject of TB and the family of bacteria to which it belongs, and that's the mycobacteria, here's a story hot off the press on a new way to turbocharge a technology that's over 100 years old, but which can be incredibly effective when traditional antibiotic treatments fail.

16:27We first met the University of Pittsburgh's Graham Hatful a few years ago when he appeared on The Naked Scientist to explain how he'd helped to treat a cystic fibrosis patient with a hard-to-manage infection using a collection of bacteriophages. These are viruses that attack bacteria that he'd isolated in his lab. But it's not always possible, even with a vast collection of these viruses like the one that Graham's assembled, to find a phage that's up to the task. So he's gone to the next level. He's developed a way to assemble entirely synthetic bacteriophages by engineering sequences of DNA that, when you insert them into bacteria, hijack the bugs and turn them into phage factories.

17:07At the moment, it is a proof of concept that it's possible, but it opens the door to developing designer phages that can rapidly be brought to bear against a range of infections. We've been studying the basic biology of phages that infect these particular kinds of bacteria that the genus is called the mycobacteria. And they're known to include a number of important human pathogens, including Mycobacterium tuberculosis, Mycobacterium leprae that causes leprosy. But then these other so-called non-tuberculous mycobacteria, which is just a whole class of these pathogens that people get as infections, often as sort of opportunistic infections.

17:50They're infections that come on top of some other underlying disease, quite commonly cystic fibrosis patients. And people with cystic fibrosis can get these various types of infections, including with the mycobacteria. And they're very hard to treat. It's a nightmare for the patients. It's a nightmare for the physicians because they try different antibiotic regimens over many, many years. And the antibiotics are quite often toxic and not well tolerated and they just don't work very well. And so people with these types of infections are really left with few options. And so we had identified, prepared and provided phages for the first treatment that we're aware of about six or seven years ago now for a patient in London with one of these infections.

18:36Since then, we've had a large number of other requests. we get a request about 100 requests a year from physicians for assistance with with with their patients and um i think that gives a sense of um the severity of these kinds of diseases and these kinds of infections because you came on the naked scientists and talked about it oh that's probably where they're all hearing about it from um graham but you saved that girl's life didn't you she was Great Ormond Street in London, and she was going to die of that infection. And your combination of phages almost certainly did at the time save her life.

19:14Isabel, who was an incredibly brave teenager, and she had cystic fibrosis and then these infections. She succumbed eventually from the various other difficulties with cystic fibrosis, the transplant and all the various drugs that she was taking. patients that have lung transplants have the least best prospects out of all of the other types of major organ transplants but she still was able to return to close to normal life for several years where she was able to achieve things that she wanted to do and to tick them off her bucket list as i said she was extremely brave and everything that we and and many others have done since would not have emerged had it not been for her and her family's bravery in taking a bold step for these what are essentially completely experimental therapies.

20:04You've got a vast library of these bacteriophages that you have worked up and when you were approached to help Isabel it was because you were able to look at the affection she had and then find appropriate bacteriophages that you happened to have that you thought would work but now you're seeking to go a step further and actually almost like rationally design a virus so that you don't have to pick and choose you can say well what do you want and i'll knock you one up how are you doing that we've become very aware of the limitations that there are for using phages for these types of infections more broadly and often when we are sent strains of the bacteria and we test them against our set of phages we don't get good hits and we're left with having to say well we're really sorry but we've looked our initial screens really didn't find any phages that might be helpful for that patient.

20:52And so we've thought a lot about what we can do about that. And although we are firing on many different fronts to try to tackle that problem, we're also aware of really what is fundamentally the underlying problem is that what we have are the naturally occurring phages that can be found in nature. And of course, nature has done a wonderful job of evolving phages to work very efficiently and effectively, but not always in doing what we would like them to do from a medicine perspective. And so what we would like to be able to do is to be able to sit down the drawing board and design the kind of phage that you'd like to have that would work broadly and effectively and would do the things better that are naturally occurring phages don't do.

21:40And so the question then is, how do you go about doing that? How do you make designer phages? How do you get to make phages and phage types that have never been seen in nature before? And so that's what we've been tackling. And there's been a number of advancements in the technologies which have been very useful to us. Two in particular that I'll just mention. One is the ability to synthesize relatively long pieces of DNA, maybe 2 ,000 base pairs, and to synthesize those even when traditionally they've been very difficult. One of those difficulties is when the proportion of base pairs that are G's and C's is rather high.

22:24And these new technologies that have been developed by our colleagues at ANSA Biotech have overcome that problem. So they can make those DNAs and then make them available to us. Secondly, New England Biolabs have developed technologies that enable us to rather simply and easily take those pieces that we've made and then put them together into the phage that we're trying to construct. And so collectively, we're able to do that. And we've done that for two completely different phages that we're interested in and have synthesized them, assembled them, and then have been able to get those pieces of DNA back into the bacteria such that they now reprogram the bacteria in order to make the phage particles that we can then propagate and study just as we would anything that we had isolated in the lab.

23:15So this is really super because now we can really make any variations of these. We can make any phages that we want to, basically, as long as we design it carefully so that it works. And the power of being able to do that engineering is really, I think, quite enormous. It feels like the sky's the limit. What a great story. Graham Hatful at the University of Pittsburgh there. Finally today we are putting tuberculosis or TB as it's more commonly known under the microscope. TB is probably one of the most important bacterial infections in the world. Estimates are that as many as a third of the global population have been exposed and it's very hard to treat and getting harder with the emergence of multiple and more recently extensively drug resistant strains of the bug.

24:01It can take months to clear the infection. Part of the problem is that we have only a single vaccine that's the live bcg vaccine which is made from a close relative of tb called mycobacterium bovis and it's quite limited in terms of the protection it affords and it's most useful only in preventing very young children from developing disseminated disease well now we know why that is and how to improve on it because brian bryson who's at mit has found that when scientists cultured the bcg to weaken it so it became a suitable vaccine the bacteria lost the ability to make some of the most important chemical markers that the immune system relies on to detect TB infection.

24:40And if you put those missing markers into a vaccine, he's found, you get back something potentially much more effective and suitable for protecting anyone at any age, anywhere in the world. Tuberculosis still kills 4 ,000 people every day. One in seven people who have lived have died from tuberculosis. And so really, if I think about making an impact on the course of human history, what would be transformative is a protective vaccine. Right now, we only have one TB vaccine that's over 100 years old. And for me as an engineer, if somebody tells you there's a 100-year-old technology that doesn't work the way that you want it to, you want to say, let's build a better one.

25:23And so that's what we've been working on for the last seven years or so. What are the shortcomings with that vaccine? That's the BCG you're referring to, the 100-year-old one? The BCG vaccine is really effective in pediatric or child populations against protecting them from their TB spreading outside of their lungs. But when you look at adolescents and adults, the BCG vaccine doesn't sufficiently protect them against TB disease. And so what we're looking to do is we're looking to make a vaccine that potentially protects against TB disease in adolescents and adults. The best offense is a good defense.

26:01And so we are looking to really design a vaccine that when you do get infected, you want to have the immune system totally ready to be able to find where the cells are that have the bacteria and handle them on the spot. What's the difference then between that and that strategy and how you want to do it and what the BCG can already do? When we think about designing a vaccine, you want to give the immune system the proteins or the other molecules that it is likely to see when it gets infected. So it's really well positioned to find the infected cells. So the BCG vaccine, unlike other vaccines that we get, is an intact bacterium.

26:46It's a form of a cattle tuberculosis known as Mycobacterium bovis that was grown in a way that through a series of mutation events lost a set of proteins that actually made it lose some of its virulent properties. So it was in some sense tamed, so it wouldn't be as dangerous as the original pathogen. But what we've actually been able to identify is that actually many of the proteins that are lost and not present in BCG are the most commonly detected proteins that the immune system sees when it's infected with TB. So it's a simple idea that if you really want to prepare the immune system to see TB, you really have to give it the proteins through a vaccine that it is likely to see when you get infected with TB.

27:37Basically, the elephant in the room is missing with BCG, isn't it? So how do you propose then to put those proteins back and make sure the immune system notices them? What's your strategy instead? Yeah, so our approach has been to really identify the ways that the infected cell tells you that it's infected. And so the way that the infected cell does this is it presents on the surface a series of barcodes, really kind of representing what's inside. And so we did that, developing some new measurement technologies to understand what happens when cells are infected with TB. and then we said let's go ahead and design vaccines that really allow us to generate the same barcodes on the surface that would be present during infection right so having identified the real linchpin molecules that say i am infected with tb and that's what a cell would display on its surface you either give that as a genetic vaccine like like the covid vaccines really or you could i suppose give the the bits of protein themselves couldn't they but when you do this and display these very specific barcode markers for TB infection, what happens?