Chernozem, he said. The Nobel laureate which discovery, I believe, is one of the most important in science history and for humanity. And he write later, it all started with Ukrainian black soil.

I have always thought about him, both in Odessa and later in the United States. He was surprised that during the vital activity of people, animal, plants, the soil was harmless to human

because we would expect it that there are many of pathogenic bacteria, infectious bacteria accumulate, however not. And this thought, these questions led to his major discovery. Of course, I'm speaking about Simon Waxman, who

was born in Novi Preluche, 30 kilometers from Vinnytsa. And in this time, as a Jew, he had a very little chance to get education, proper education. However, his mother, she fight for this,

and then she also privately teach him at home and that he had a chance to learn in Odessa. And then in age of 22, he emigrated to the United States. He got the Nobel Prize for the discovery of streptomycin,

the first antibiotic effective against tuberculosis. But I believe that his discovery of the group of bacteria about which we will speak today is way more important than this one antibiotic for which he got the Nobel Prize.

And he appreciated Ukrainian people. He was very touched after he became famous already, going back to Ukraine to Novi Preluche and speaking with the simple field workers and remembering his childhood there. His son Byron said, he's here,

said that when we have been at the concert, at the performance, Simon, my papa, felt asleep all the time because he has a thin ears. But when he arose and he came back to our garden and he took handful of earths and he always said that this habit he got from Novi Preluche,

from the field workers, and this inspired him to become a soil microbiologist. Why this is so important? Because antibiotics, I believe they are the success story of all times. You can see, so without antibiotics, our life expectancy would have been around 47 years.

Okay, 46 for men, 48 for women. And I would need already to worry a little bit about this. And also the mortality rate decreased significantly, considerably, with the invention of antibiotics.

You see that this is the cause of thirst due to the infectious diseases. And this is how it's raised down, decreased down, when the antibiotic had been invented. We are in Germany, and I want to also to appreciate

and to thank another big microbiologist, the German microbiologist Paul Ehrlich, who was the first with the idea of antibiotic. And he invented indeed the first antibiotic which was brought to the market in Germany. There, of course, these two men are very well known

as very famous scientists. But the history of antibiotics has a lot of hidden heroes. From about those, no one is speaking anymore. And one of those is also another Ukrainian scientist. You probably don't know him. It's Marian Wojciechic, Riko Wojciechic.

He's son of Ukrainian immigrants, Peter and Marta. And he discovered a very important antibiotic called gentamicin, which is still now used in clinic, and is one of the last resort antibiotic against systemic diseases. And he discovered this occasionally in his cellar

being not professional. And then he shared his thoughts with one of his friends from Sharingplu company in US, and they patented this without citing him. So then he went to see you, and after several years, he got paid royalties around of $2 million,

which 65 years ago was quite a lot of money. And he was recognized as an inventor of gentamicin. Niko, or Riko Wojciechic. So we have a lot of names, we have a lot of groups of antibiotics, and one might say, okay, the problem is solved

with the pathogenic bacteria with infectious diseases. However, as you see from this slide, the problem is really huge to date. So we are facing the situation that we have many bacteria which are resistant to all currently marketed antibiotics.

Some statistic here. So you can see how quickly, from 2003 to 2016, we accumulate multi-resistant bacteria over the Europe. And this red, I think 2023, much more red colors will appear here.

And red means that we have in hospitals bacteria which cannot be removed by any kind of antibiotics which are marketed to date. And this is really dangerous. And this is not somewhere in the third world countries. It is here in Europe, so we have a lot of cases when I'm speaking with physicians

from hospitals, for example, from Hamburg, 30 kilometers from Saarbrücken, they say the woman 50 years old is going to Turkey, get some scratch on the hand, get infected, a completely healthy woman, and dying after three weeks from multi-resistant stuff outros.

So this is here. If nothing about this will be done, so this is our perspective, that until 2050, way more people will die from infectious diseases, even in comparison to cancer, which is now this perspective. So you see how very high-resistant pathogens

are accumulated in Europe. So we are speaking about so-called silent pandemic. So you can compare the pandemic situation with COVID-19 was a lot of attention, it was a lot of efforts to get rid of this,

but we have a silent pandemic which are slow but steady spread, and we need to do something about this. So the situation is following. The situation is following. We are coming to so-called post-antibiotic era, which means that every problem, every strep throat,

every scratched knee could kill once again as before the era of waxpan and flaming. So I hope you got this message that this is really a dangerous situation which is coming, and now a little bit about the factors which caused the situation.

What is the problem here? So of course globalization, people are traveling a lot, the resistance is spreading a lot, extensive use in hospitals especially. However, it is still very extensively used antibiotic in animal husbandry. And the problem is that antibiotics in animal husbandry,

the classes of antibiotics are the same which are used for curing people. So if you think of amount of antibiotic use, you see that three times more antibiotics will be used to treat animals in comparison to people. So for every kilo of meat, for example from swine,

you need to give approximately 170 milligram of antibiotic which is quite a lot. Then if you think of German eating meat, then you imagine how many antibiotic at the end of the day we are consuming.

Also in 2006 in European Union, it was forbidden to use antibiotic as feeds for animal. So in this caustic world, people are always finding the way, so we are not feeding them now, we are just curing them very often, right? So if one chicken here is ill,

the whole stall gets cured with antibiotics. So in fact, also a little bit the amount of antibiotic have been reduced, it is still a significant number. So be careful if you take the raw meat to your hands because surely, statistically,

you have a lot of multi-resistant bacteria on the meat. So if you treat it then and eat, it's not dangerous. But to keep it in hands, it really can be dangerous. Also in Germany. So one can expect, okay, we have a huge problem. We have a spread of resistance and that means that industry, that society

would spend a lot of effort to find novel drugs, novel antibiotics. But the situation is absolutely opposite. So resistant bacteria are on the rise and the antibiotic development are on the fall. So I show you here, this is the area, Waksman era.

So this is 50s, 60s, where antibiotics classes have been developed very intensively. And this is last two decades. We don't have any new classes of antibiotics being developed. And this is essentially important.

So we have so-called development gap. So what is the reason? So many reasons, but few will just look around a few of them. So you know that it is very difficult and very expensive to develop drugs. There's some numbers here. So this is preclinical trials. This is millions of dollars.

Clinical trials, all together we are ending up with a round of one billion euros, right? And so now if you look on the revenues, spending is selling these drugs. So this is cancer treatments. If you develop drugs, you get this profit and this antibiotics.

So no wonder that big pharma, big companies, they absolutely clearly will leave the field because they don't have any profits. So they're developing drugs which will be likely not sold because it will be last resort and keep until the end, until all other antibiotics are not working.

And now we are thinking on the investment. This is total value of all antibiotics prescribed in Germany. And this is sales of one single anti-cancer drug in Germany per year. So this is annual R&D cost of 10 biggest pharma in Europe.

These are marketing costs. And these are costs and funding, you and US, for the discovery of antibiotics. They're absolutely not appreciated. And one need to do something about this, despite on their importance.

Of course, a German government, so they spend a lot of efforts and they are one of the biggest founders of an early antibiotic discovery. This Deutscheszentrum infection, Warshak and so on and so on. However, we need companies doing this because there are special skills when we speak about clinical trials,

where only big pharma can pick it up and do it further. So resistance is really important. Antibiotics are not being developed. We have seen the economical reason for that, which is very clear. But it's not only this. We have also technological, also scientific problems

involved with antibiotic discovery. So these are bacteria which have been found by Salman Waxman, actinobacteria. They produce 70% of all marketed antibiotics, which we have to date. That's why his discovery was so important till now.

These are very complex molecules and they are practically impossible to synthesize chemically, so one need to rely on bacteria producing them. And what usually scientists, what usually companies were doing, they were going to interesting place. For example, this my partners from Lviv

by prospecting in Ukraine, in Crimea. And they are collecting soils and then doing the most difficult job, of course. And PhD students in the lab, they're having fun, isolating the bacteria from this soil, collecting soils. And afterwards, doing some analysis, just not relevant,

analyzing these compounds which are produced. Oops, I hope, yeah, back, yes. And then afterwards, they're isolating compounds. The problem, however, is that there's a huge rate

of rediscovery of known compounds. So we can work two years until certain point and you understand that you have found antibiotic which was found by Salman Waxman 60 years ago. And this is a huge problem. And this is also one scientific reason why the big pharma left the field. It was way too expensive.

And so there was even the idea that actinobacteria, they are already exhausted source of antibiotics. There's nothing to find, right? And there was a lot of discussion, scientific discussion in papers, in literature. However, if you look on the sky,

so do you know how many stars you can see with the naked eye? Approximately 500. So but you intuitively believe that there is a bit more, right? So it's a very similar situation with antibiotics and natural products. So if we decipher the genomes of this actinobacteria,

we are not going to the details. When we sequence these genomes and analyze them, we see the huge potential of these bacteria to produce more. And this is now the biggest challenge in the field to exploit and explore this biosynthetic potential, right?

To get access to this chemical diversity because it's just simple numbers. So the usual average bacterium would produce five, six compounds, but they have a potential to produce 50, 60. And we need to get access to these molecules, to these chemical entities.

So and I will speak about this, how one can get it. So I will tell a small, just very briefly of course, the approach we are doing, pushing in our lab to get access to this chemistry. What do you think? Why is this bacteria are not producing antibiotics under the laboratory conditions? It's very simple.

Imagine that you need to express many genes. It costs a lot of energy. And we would like always to save our energy. And bacteria do as well. So they produce them only if they need them. And these conditions are very specific in soil. So many factors, temperature, UV, humidity,

a specific combination of metals and so on, they lead to the expression of these genes and production of antibiotics. So it's impossible to reconstitute in the lab. So and our idea was that we say, okay, if it's impossible to target

this very, very complex regulatory network, let us just to cut it out and to decouple the production of these antibiotics encoded in the corresponding genes from the network and then start producing. So that's so-called synthetic biology approach.

And every research, every science, every discipline is going through this three different stages, the age of observation, the age of analysis and age of synthesis. And the biology is one of the last because physics is far away from biology.

They are already an age of synthesis since 50 years, 60 years. Chemistry as well. And biology is only approaching. We are working a lot on age of observation and analysis and now we are in the age of synthesis. What does it mean? That mean for the, in terms of antibiotic discovery, we said, okay, let's do following.

Let's think on genes. Let's get access to the genes which are responsible for their production and then bring them to the specific organism, to the very simplified organism called chasis where they will not have this regulatory network where they will produce this higher likelihood.

In addition, we can, so-called, I have tried to find the words, the simple words for that. We can also synthesize so-called regulatory elements which will for sure drive the expression of these genes in this chasis, right? We have three components. Genes responsible for the production,

an organism, a simplified organism where these genes will be brought in and then the regulatory elements which will ensure their production. So when we started to think which kind of chasis to choose, I always liked this idea of domestication. We have approximately 5,000 higher animals

but only 50 of them have been domesticated, not by chance because the rest are not really good for domestication and it's the same with bacteria. We have Bacillus subtilis, Pseudomonas putida, we have Saccharomyces cerevisiae, E. coli and so on but we have way more bacteria than animals, right? And our idea is to develop such a domesticated bacteria

but even more, we want to go further more. We want to develop engineered bacteria which is fully controllable and can ensure the production of antibiotics. And here I would like to show our principle. I call it Michelangelo principle or 3M principle.

Why 3M? Because the postdoc who is doing this job or who has done this job was Maxim Mironovsky Michelangelo. So, and this was very easy. We have found such a bacterium and we just removed everything which was unnecessary, right? Which was, which to stop the production and so on.

It's a long process. It's a seven years work which I will present in one slide but just your take home message is so you make a simplified bacterium, simplified chassis where the production is much more easy to monitor, much more easier to find and much more easier to push these genes to express over there, right?

And the same principle. So we just took everything unnecessary and we have got our ideal bacterium. So we have many genes which are not necessary there and step-by-step, iteratively, it's one slide, one and a half minutes but it was done in seven years. We have found, we have discovered or engineered actually

the chassis where the production is much more efficient. I show you here. So these are a clean background. So those who knows chemistry a little bit, analytical chemistry can see that in this chromatogram you barely have some compounds and this is very easy and to find a new one. So we have such a chassis

which is already driving a little bit and I want to show. So at the end we have developed and best in class methods for assembling, cloning these bicentennial gene clusters responsible for antibiotics and now it's gone. Remember, so these are genes which are driving production of antibiotics. This is our chassis which we worked for a long time on

and some controlling elements. And bingo, we have found, we have discovered for the last four years with limited resources, more than 200 novel compounds using this approach.

Just to tell you that people are happy if they find one with the whole group. We have found 200. We have shifted the bottlenecks from discovery to structure sedation, isolation, activity testing and so on and so on. And this is only start. And as the fate always wants,

the most promising compound, uranium fatty, let's say, latine, so was coming from crim. So we have found the bacterium, we have cloned the gene cluster which was very unusual, we have expressed it and found the compound which was amazingly active and not very toxic.

So it was a compound that was super active against Pseudomonas, against Acinetobacter baumannii which is one of the biggest threat in hospitals, right? So we are working further and what was even more interesting, this compound is absolutely new. So it's not new, it's novel, right? The old combinations of elements

in this compound is absolutely novel. I cannot really show it here because we are going to patent this but this again came from Ukraine, from Ukrainian strain, Ukrainian DNA, discovered in Germany. So with this, we are coming slowly to the end and this is, I hope I could address you

this first challenge. So the first challenge was to find, to discover a new diversity, to open a new chemical space and using synthetic biology approach, we opened this new chemical space and discovered a huge number of novel chemical entities but this is only one challenge.

The second biggest challenge is to, you know, if you look on this again, right? You see, okay, you know already there's many more than 500, that's good but even stars are limited. So I don't know how they counted but I believe they say it was like 50 billions of stars

in the galactic, so I believe just and that means that they are limited as well as antibiotics, as natural products are limited resource and we need to treat it preciously as forestry, as water, as energy because it's limited. And then I am coming to the second challenge.

During the last 70, 80 years, a huge number of antibiotics have been discovered but discovered does not mean developed, right? So for example, this one was discovered when I was two years old. This was discovered when my mother was three years old but nothing happened to these molecules

because scientists and pharmacists, they do not have access to them because the bacteria are producing them in such a limited amount and you need to spend so much effort to get this compound overproduced and to test them, to test toxicity, to go for pharmaceutical development,

you need a lot, right? And this stops researchers and also big pharma to go for that because it costs a lot and so on. Just one slide, we have used this, our approach with our chassis, with these genes responsible for those compound, there are many, I just showed two

where we are working with a big industry on them and we could produce them hundreds times more with relatively simple methods and this gives a chance using this method for this compound to be developed. So two ways to discover novel

and to explore existing already but not developed further, right? Yes, usually on this point, I would thank my group for doing perfect research, blah, blah, blah, which is true, they really do and I'm showing where we are in Saarbrücken

and all this funding and so on but I recognize this year that we publish the fewest paper, number of paper since IMAPI in Germany and of course, I would also show how we are greatly spending our out seminars in Mallorca, Alps, Ukraine and so on

but this year, 80% of our times we were doing this, we are not doing our research and I'm really, really thankful to all people involved. This is a technical director of Roche, this is CEO of Explogen and this is teacher of sport from my village and they're all three helping and bringing humanitarian aid to Ukraine

and this was really tough year, still going to be tough but what I recognize, we are much more than our profession we are not constrained by our expertise, we are much more and what I learned also from my collaborators from big companies which I never believed that they will stand with us

with such a huge efforts, people bringing money to my office on envelopes leaving and I even didn't know who made this so we bought a lot of medicine and we are still doing this, driving to Ukraine, bringing this to those who are in need, I'm really thankful for that and thanks to you for your attention, slavo krijni.