Old active substances against new resistance

The discovery of penicillin was a turning point in medicine: diphtheria, plague, cholera could be cured. But the victory of humans over the bacteria is not lasting. Now, as the miracle weapon threatens to become dull, it is remembered: Did not we know other remedies back then?

That could become such a real disgusting topic again today. Today I am on the way to hunting phages. Bacteriophages, bacterial eaters. And they are also found particularly well where there are many bacteria, such as in a sewage treatment plant. That’s why I packed my rubber boots and am on my way to Braunschweig to meet an expert on phage hunting. It’s a bit out of the way, I’m now heading for a big sign: Science Campus Brunswick South. And there I seem to be right. I just hope that the whole thing will not stink too much today. ”

My goal in Braunschweig is the Leibniz Institute DSMZ. In 1928, the penicillin was discovered. In the period before, the physicians were by no means powerless against bacterial infections. The old concepts, however, have been swept away by the resounding success of antibiotics. Meanwhile, it looks a little different: The antibiotics are not as good as they once were, because the bacteria have developed resistance to them. And so you remember again supposedly traditional therapies.

“Good day, you are Mr. Reuning?” – “Yes, exactly. Hello. “-” Christina Rohde. Welcome. “-” I’m glad. “

Tiny little things that once had great hopes are bacteriophages. And they store here, in the German Collection of Microorganisms and Cell Cultures. I’m in contact with Dr. Christine Rohde.

“I do not know, I brought my rubber boots. Will we need them? “-” Well, I do not have any. I hope not.”

Bacteriophages are viruses. Viruses that do not affect us humans, but bacteria. For this purpose, they anchor themselves to the surface of the bacterium and inject their own genetic material into the cell. A hostile takeover, because the bacterium now produces the next generation of phages inside. Until it eventually bursts and emits a swarm of phages – who then board the next bacteria.

“We are here in the DSMZ phage lab, and this looks like a lot of work. It is quite full. It’s all because we’re working on phage samples and isolating new phages from environmental samples, “says Dr. Christine Rohde.

The trick: the tiny hooks of the phages are highly specific. There are phages that attack only staphylococci. And those who are after pseudomonades only. Or on salmonella. Or on coli bacteria. Unlike antibiotics, treatment with phages does not harm the beneficial bacteria.

The principle would be perfect to supplement the flagging antibiotics. But you always have to find a suitable phage in the environment for every germ. That’s exactly what Christine Rohde’s job is: she’s looking for something. And for that she first needs a device that looks like a broomstick.

“That’s what now?”

“This is a professional sampler. If we go to the treatment plant or ponds or rivers to take water samples. ”

” Looks like some household appliance, a scrubber or something. But now comes a beaker in front. ”

” Yes, we have a beaker here. That has to be done here. And then we can draw from the depths. Then we’ll take another bottle. “

And then you can start. Fortunately, not in a sewage treatment plant, because right behind the DSMZ building, we can also find something.

“We now draw a liter of pond water!”

“We are now here on the institute grounds at a small pool. He is a bit overgrown. Can we get there at all? ”

” Oh, but that’s really … ”

And then the next surprise, as we approach the wooden jetty that protrudes into the pond.

“Oh, that’s locked!”

“But you can get there.”

A red and white barrier blocks access. Well, but what do you do not do in the service of science? So get away with it.

“Maybe the jetty is already a bit rotten. Maybe I would have the rubber boots. ”

We make our way through the reeds and enter the slippery platform.

“So, we draw now a liter of pond water in the hope that there are some nice new phages in it. The water looks relatively clean, but that has nothing to say. Of course, it always depends on which bacteria are in a body of water. And frankly, I do not suspect, for example, Staphylococcus aureus in large numbers. Therefore, we will not find any phages here so easy against staphylococci. ”

” I had expected that somehow we go into a sewage treatment plant. Is that your typical job? “

“Yes, we go to the sewage treatment plants in the area about once a month. But even the sewage treatment plants are not enough for us. We’ve been going into clinical wastewater for a year or two, yes. Because that’s where the variety of clinically significant bacteria is much bigger, and also the likelihood of getting suitable phages. “

Already in 1917 there was a phage preparation

In the search for alternatives to the ineffective antibiotics, researchers now look back to the time before the discovery of penicillin. Because even then there were therapies against bacterial infections. The phages belonged to it.

In 1917, a phage drug was supposed to help cure patients with bacterial dysentery. Now they are rediscovered, says Christine Rohde. But why did not you start earlier?

“We were just spoiled by the antibiotics. And the antibiotics can not or will never be replaced by phages. The phages will supplement but not completely replace antibiotics. And that’s not our goal. Well, you forgot it. The phages have remained in the sinking because the antibiotics actually worked quite well. Most of the time, they are fortunately still working. ”

” Which drugs are already available based on bacteriophages? “

“Actually, we have the situation in Georgia, where Georgia is really very special, we have pharmacies approved in about six hundred pharmacies and approved by the Georgian government. Anyone can buy those over the counter. And the Georgians still make patient-specific preparations on request or for special individual needs. “

” What does it look like outside of Georgia, here in Germany, for example? “

“In Germany, we actually start relatively new, although in Germany Phagentherapie run on a very small scale in a clinic in Hamburg until 1984. But otherwise is almost no phage therapy in Germany. I can not give concrete examples now either. There are rare cases of phage therapy, but it’s just not approved. And now we have to take the approval procedure together with the licensing authority and of course then go to the European level, the EMA. “

“Phages are biological entities. They have genetic material. Genetic material can be changed. Is it even possible to admit phage as a drug if you do not even know what happens to these phages, I say, drugs? “

Do not use genetically modified phages

“Yes, phages are a biologic or will be counted as biologics, that’s clear. A phage can also mutate, but one should not imagine that the phages mutate back and forth and criss-cross and constantly change themselves. And anyway, our intention is not to use genetically modified phages in the near future anyway. So that fits so far. And there is no reason for fear, because we are constantly testing the phages genomically, that is, with regard to their genetic material. And there we can look very bioinformatic every phage very carefully. ”

” Is there already a candidate for a phage drug in Germany? “

“Yes, at the moment we are actually developing phage preparations or a cocktail, we call this a phage cocktail to be used in CF patients, cystic fibrosis, or bronchiectasis patients. Namely, the phages should be administered by inhalation. This is a cooperation with the Charité in Berlin and also with the Fraunhofer Institute ITEM here in Braunschweig near us. So we are in the middle of it. And it’s supposed to be a clinical trial in the narrow sense. “

Phages as a supplement to conventional antibiotics. For the post-antibiotic age, inspiration is gained in the pre-antibiotic era. And some researchers even go a step further, such as the company Lysando in Regensburg. There, ingredients of the phages are further developed into tailor-made antibacterial agents. The rubber boots have stayed at home. I do not need that for a harmless lab visit.

“In the beginning I have to point out that we work here with human pathogenic bacteria, which could be dangerous for humans as well”
“Oh dear!”
“As far as we are, everything is clean. So as soon as you do not touch us, et cetera, you are actually safe. And as long as you are healthy, the visit with us now no danger there. ”

” Okay, I am healthy. Let’s hope it stays that way and just drop by in the lab. ”

” Gladly! ”

And then Martin Grießl hands me a white coat that feels like it’s made of a thin nonwoven fabric. A disposable smock, which is disposed of after my visit to the lab, explains his colleague Manfred Biebl.

“He then goes directly into the contaminated waste, is autoclaved and disposed of. Okay, let’s start with the microbiological part of the lab right here. “

Test effect of artilysins in the laboratory

The two scientists run the research and development department at the Regensburg-based company. They do not deal with the phages themselves, but only use tools of the viruses: those molecules that weaken the cell wall of the bacteria so much that the protozoa burst under their own internal pressure. The biologist Eva Schirmeier demonstrates in the laboratory how the effect of these Artilysins in a sample vial can look in the laboratory.

“In front of us we see two glass jars, each containing one milliliter of cloudy liquid. This fluid contains bacteria of the genus Streptococcus. These are known to cause tooth decay or ear, nose and throat infections. This turbidity of the liquid comes from the fact that the bacteria are present in a very high concentration. So, there are one to ten billion bacteria in one milliliter of fluid. In the right vessel, there is ‘buffer’ over it, because the doctor is pipetting. Cornelissen a control solution purely without Artilysine. And in the left vessel, there is Artilysin before, she pipetted a solution with Artilysinen. ”

” Great , it has not been injected, we are sure. “

“The right solution, which contains just the bacteria with the control fluid, which remains cloudy. The left vessel with the cloudy liquid and the artilysin solution now clear gradually. The explanation comes from the fact that the Artilysine destroy the cell wall of the bacteria and burst the bacteria, so to speak. So you can imagine it like a balloon or a car tire, in which you stab with a sharp needle or with a sharp object. “

This even works with the dangerous Gram-negative bacteria. Their cell wall is particularly robust and therefore forms a barrier to conventional antibiotics, which usually have to get inside the cell. The situation is exacerbated by the fact that especially among these gram-negative germs, the resistance has increased significantly in recent years. With the help of Artilysine, they were also able to fight effectively.

“Well, now on the right side you can still see a haze. It has not changed since the beginning. On the left, the solution is now completely clear, so that one can now just say: This one to ten billion bacteria, an immense number, is now completely killed. “

The Regensburger company does not develop ready-made medicines. The Artilysine represent a drug platform. Each substance must be tailored to the specific application of the customer, for example, to a specific group of bacteria. The modified phage tools are not antibiotics in the classical sense, says Markus Graf Matuschka of Greiffenclau, the chairman of the board of directors of Lysando AG.

“Our technology has technically solved the antibiotic problem. That’s right, antibiotics as technology are already over seventy years old. And the discoverer of the antibiotics, Fleming, Sir Fleming, has already pointed out in his Nobel Prize speech in 1945 that resistance will come. Nobody just wanted to listen. And this system is a mathematical model. You now have so many percentages of resistances that you can not get away from it. And it is absurd to assume that you could solve the problem caused by antibiotics with antibiotics. That is absurd in itself. ”

So far, there is no resistance to Artilysine

The known antibiotics often sabotage the metabolism of the bacteria by interfering with their complex biochemical machinery. In contrast, the bacteria have developed strategies, resistances: they degrade the antibiotics with enzymes, flush them out of the cell with molecular pumps or rebuild their metabolism. A constant race between man and bacteria. Resistance to Artilysine, however, has not yet been observed by Lysando researchers.

“Not only did we not observe anything, but we tried to provoke resistance through third parties, of course. And until today, no one has been able to provoke resistance to an artilysin. There is no resistance to Artilysine until today. This has a whole lot of reasons. I would like to point out once that the bacteria have no time to exchange resistance genes with each other, because Artilysin acts in contrast to antibiotics in a fraction of a second. Antibiotics take several days because they sabotage rather than just scrapping as we do. ”

” When do you expect the first products on the market with this ingredient in or with this drug class? “

“We expect the first products from the end of 19, early 20 in the field of animal applications, animal pharmaceuticals. For example, dentistry is an issue of selectivity, preserving the microbiome, the healthy microbiome. And another topic is wound care. Heavy, deep wounds, in which more and more people suffer. Also there will be a product with artilysin on the market. ”

In addition to the phages and their tools for destroying the bacterial envelope, a look into the history of medicine also reveals other methods of rendering pathogenic germs harmless. And you do not even have to kill them. Sometimes it is enough to take their weapons – so that they can do no more damage in the human body. Such an approach has been pursued by the MODIFY medical study. What this involved, I would like to be explained by a researcher who was involved.

Oliver Cornely is Professor at the University Hospital Cologne and Center for Clinical Studies. In the MODIFY study, he dealt with the hospital germ Clostridium difficile. And the handling of this protozoa is actually difficult. Because the bacterium can cause severe diarrhea. This usually happens in patients who are being treated with antibiotics.