New antibiotics - The fight against resistance

00:00:00: How do bacteria and viruses trigger diseases?

00:00:08: How does our immune system defend itself against them?

00:00:11: And what must active substances be able to do to fight dangerous infections?

00:00:17: The Helmholtz Center for Infection Research, HZI for short, is looking for answers to these

00:00:23: questions.

00:00:24: How this research works?

00:00:25: How the results are used in medicine and who the scientists are that work on all these

00:00:30: topics?

00:00:31: This, you can listen to here at Infect, the podcast of the Helmholtz Center for Infection

00:00:37: Research.

00:00:38: In this episode, our host Julia Dehmann, biologist and science journalist, talks to Dr. Mark

00:00:44: Braunstrupp.

00:00:45: He is a professor of chemical biology and at HZI, he and his team research for substances

00:00:51: to counter antibiotic resistance.

00:00:56: Mark, before we talk about what exactly you are researching here at the HZI to tackle

00:01:02: the problem of antibiotic resistance, I would like to hear more about what brought you here.

00:01:08: You spent a long time doing research in the pharmaceutical industry as a chemical biologist

00:01:15: and now you're here.

00:01:17: Why?

00:01:18: Well, I like research.

00:01:19: I like discovering things and I was intrigued by infectious diseases and I was looking for

00:01:27: an environment where you could conduct infectious research or infection research with a long

00:01:35: perspective and with a long breath and Helmholtz and the HZI offered this opportunity, not

00:01:44: doing short-sighted research over whatever two, three years, but they really develop

00:01:50: perspectives over seven or even beyond 10 years.

00:01:56: This I found very convincing and therefore I decided actually almost exactly 10 years

00:02:00: ago to join HZI and leave industry.

00:02:04: What exactly does a chemical biologist do?

00:02:07: We try to resolve biological questions, in particular cell biology, question using small

00:02:15: molecule tools.

00:02:16: That's I would say the tight definition of the field.

00:02:20: Well, the HZI does research from the active substance in nature or in its natural environment

00:02:27: or at the bench to the drug at the patient's bedside.

00:02:32: Is that what you mean by a translational research?

00:02:35: Yes.

00:02:37: I would say is a broad description.

00:02:40: Maybe I'd like to add two things.

00:02:43: First, what you describe is this process from so-called bench, the lab bench to the bedside,

00:02:49: but translation also goes back from bedside to bench where you carefully observe why do

00:02:56: treatments fail and what research questions arise from that.

00:03:03: That's one part.

00:03:04: Then maybe the somewhat tighter definition of translational research, I would say goes

00:03:11: to a somewhat later stage where you really ask why do some people get sick through which

00:03:20: mechanisms and are these the same for all patients and which drugs are needed for which

00:03:27: patients?

00:03:29: It's about patient's certification, finding biomarkers and also finding the right drug

00:03:35: for the right patients.

00:03:36: I would say that's the heart of translational research.

00:03:40: I wouldn't spend it really from A to Z and then we all do kind of translational research.

00:03:45: I think that's too broad for my sense.

00:03:49: So it's very individual and it's very, very detailed.

00:03:53: What exactly are you researching at the HZI?

00:03:56: I'm heading a department for chemical biology and we are trying to discover and optimize

00:04:02: and characterize novel anti-infectives.

00:04:06: These are mostly novel antibiotics, substances active against bacteria, but in the past three

00:04:11: years we also did more and more antiviral research and we are trying to find new so-called

00:04:17: least substances.

00:04:18: We also optimize their properties that they not only act in a test tube but also say in

00:04:25: living organisms in animals and then later in humans.

00:04:29: But beyond that we also try to understand how they work mechanistically.

00:04:34: So what their so-called mode of action is.

00:04:37: And what would you say is your greatest research success?

00:04:40: Yeah, it's a difficult question.

00:04:42: I would say if I look over these past 10 years I would say it's about setting up a platform

00:04:50: of tools that allow to bring substances to the site of infection and also especially

00:04:57: inside a bacteria.

00:05:00: If this sounds too general maybe I can also highlight two concrete substances.

00:05:07: One antibiotic compound that we optimize together with many groups at HZI, especially

00:05:13: Rolf Müller's group, the so-called cystobactamids where we now really have very advanced compounds

00:05:18: and maybe even more advanced.

00:05:22: I'd like to highlight a patoblocker project.

00:05:24: This is about compounds that don't kill bacteria but that disarm bacteria that prevent the

00:05:32: bacteria from becoming pathogenic, so from making people sick.

00:05:39: And here we have substances that help to defeat lung infections that are caused by

00:05:44: staphilococcus aureus.

00:05:46: That's one of these really dangerous pathogens.

00:05:49: Could you tell more about the platform?

00:05:51: Yeah, the platform, as I said, it's about bringing drugs into bacteria.

00:05:59: And here we follow one strategy that is called the Trojan horse strategy.

00:06:03: And indeed it works in the same manner that the Greeks used to get into the castle of

00:06:13: Troja in this ancient story.

00:06:18: So what we do is that we offer the bacteria an essential nutrient.

00:06:24: These are iron ions.

00:06:27: We offer the iron ions, so the horrors are so-called Zidro force.

00:06:32: These are small molecules.

00:06:34: But then we couple a toxic antibiotic to the Zidro force.

00:06:39: And in the same manner as the people of Troja kind of thought, oh, it's a great horse,

00:06:45: and they dragged it into the castle, which is hard to defeat otherwise, the bacteria

00:06:51: drag this conjugate inside the cell, which is hard to defeat.

00:06:56: hard to penetrate otherwise. And then when they're in, they recognize, oh gosh, there's

00:07:02: the antibiotic in there. And we kind of refined these tricks and made it more general.

00:07:08: It's a really good trick, it sounds like. But this special research, how is it funded?

00:07:18: Well, first of all, it's funded by Helmholtz. So we are in a fortunate situation that we

00:07:27: get good and stable base funding. And I think this is really needed for this kind of research.

00:07:36: But on top of that, drug research is quite expensive. Therefore, we also have to look

00:07:40: for third party funding to push selected projects into these translational stages.

00:07:48: When I think about how detailed this kind of research is, I mean, it takes ages and

00:07:55: certainly costs a lot of money, antibiotic research. How long does it take and how much

00:08:04: does it cost?

00:08:05: Yeah, it's, I would say it's quite variable. There's no fixed number. But if you're fast,

00:08:12: it still takes between 10 and 15 years from the early research phase until a true drug

00:08:20: on the market. But this is only the case if you always have money and if you always have

00:08:26: the power to push the project forward. What I also have to say that is especially the

00:08:31: academic setting where product development is not the only focus or maybe not the prime

00:08:38: focus, the projects go often even slower because you don't have all the people and all the

00:08:45: money required to push it forward. So in the academic setting, you can even add a few years

00:08:51: to this 10 to 15 months. And drug development is very expensive. I would say that you have

00:09:00: to spend several hundred million euros before the drug gets to the market. And this is only

00:09:05: the sum that you have to spend for the successful project. However, many projects fail in between,

00:09:13: for example, during clinical development also during preclinical because they're not active

00:09:18: enough or they turn out to be too toxic. And then you have invested quite a bit of money,

00:09:23: but no drug in the end, but just a terminated project. And of course, you also have to pay

00:09:28: for this say attrition. If you count this also to the R&D costs, you end up with an

00:09:35: amount of one to two billion euros per drug on the market. So it's really expensive. However,

00:09:44: still the value to society justifies even these large investments.

00:09:50: But not every drug is really successful and not every drug is used. That means it's not

00:09:58: really profitable for the pharmaceutical industry, is it?

00:10:01: Especially the area of antibiotics is not profitable. And this is a problem. Maybe it's

00:10:09: the biggest problem of say antimicrobial research these days. And this is for two reasons.

00:10:18: First of all, I said, okay, when you made it in the end, you have a drug and this is

00:10:22: a big value for society. But this is not fully true or not permanently true for antibiotics

00:10:30: because of antimicrobial resistance. So bacteria that become resistant decrease the value and

00:10:39: the utility of a drug over time until it vanishes completely. So this makes it more problematic.

00:10:47: And this induces a need to come up with new antibiotics again and again and again. And

00:10:55: the second argument, in order to say slow down this value decrease and in order to slow

00:11:02: down resistance formation, a new and fully active antibiotic is not used as widely as

00:11:10: possible. But it's kind of say hidden in the shelf and it's only used for those patients

00:11:16: who have say no other options. But this means that you don't sell a lot of quantity for

00:11:21: this drug. And this is opposite to all to the prevailed market mechanisms, right? If

00:11:30: you have a new product, you sell as much as possible. And then you make money by these

00:11:37: large sales volume. And with the antibiotics, okay, you have something great, and you try

00:11:42: to use it as little as possible. This doesn't work. And therefore we need fundamentally

00:11:48: different mechanisms to make antibiotics also attractive or viable, even viable from an

00:11:54: economic perspective.

00:11:55: What is being done internationally to combat the multi-resistant pathogens if the pharmaceutical

00:12:01: industry withdraws? And what new research ideas are there from a global perspective?

00:12:08: Most of all, say the big pharma players were replaced by smaller biotech companies. But

00:12:16: in the end, they faced the same market mechanism. So we also observed that they go bankrupt.

00:12:22: And therefore, yeah, we have to change the economical mechanisms in this area. What has

00:12:30: been done say on an earlier research and development side is that say new consortia and new public

00:12:38: players have risen organizations like Carpx or Guard P. Also in part Bill and Melinda Gates

00:12:46: Foundation or the AMR Action Fund have been created. These names were these are all new.

00:12:54: They all didn't exist 10 years ago, and they have taken over antibiotic research and also

00:13:00: antibiotic development to some stage. And this, I think, is starting to fill the void.

00:13:07: And therefore, I'm optimistic in terms of say new innovative solutions that I even tried

00:13:14: in patients. But the problem with the say market attractiveness yet has to be solved.

00:13:24: Okay, it's an open question. And we hope that this will be saluted. We hope so. Thank you

00:13:34: very much for the interesting talk.

00:13:37: Thank you.

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