“Total synthesis is like a jigsaw puzzle. The structure of the molecule is composed of individual “pieces” which we have to prepare and put together in the right way,” explains Ondřej Kováč from Palacký University in Olomouc. In November, Ondřej is set to leave for a one-year research stay at Innsbruck University in the lab of Professor Magauer, where he will focus on the total synthesis of a new antibiotic known as kibdelomycin. This antibiotic has a unique mechanism of action compared to others known to date and could also be effective against resistant strains of bacteria.
Nobel prize-winners often have interesting stories about how they learned about their award. How was it for you when you received a stipend from the Experientia Foundation?
At the time, I was at home working at my computer and opened an incoming email. I was obviously extremely delighted, as I had really wanted to obtain the stipend. And I was a bit surprised too, because I hadn’t expected the results to arrive so soon. Actually, the whole week was rather eventful and positive. I was finishing writing up my PhD thesis; my son was born on the Saturday; and on the Monday I learned that I’d received the award.
When and how did you first learn about the Experientia Foundation?
It was two years ago at the Interdisciplinary Meeting of Young Biologists, Biochemists and Chemists in Milovy, where Dr. Irena G. Stará (Chair of the Board of the Experientia Foundation – author’s note) delivered a lecture. I found it very interesting and looked up more details. The story of the Experientia Foundation is extraordinary and unique. I read all the profiles of the stipend award winners and wanted to become one of them.
Do you have any recommendations for other stipend applicants?
I recommend visiting the lab you want to go to in advance. For me, this helped a lot in the decision-making process, because I was choosing between several places. It is also definitely a good idea to start early and have enough time for the project. Coming up with the idea and designing the experiments is what takes the most time. Writing the project itself is the easiest part. And I certainly advise that you should not be afraid to just give it a go.
How did you choose the research site you are going to?
I was looking for a group where they do total synthesis, and there are not many of those in Europe. I met Professor Magauer two years ago at a conference in Vienna. I was intrigued by his projects – he performs very elegant chemical reactions to prepare complex molecules. And I also had a personal recommendation from Professor Waser from Johannes Kepler University in Linz, where I had been on a six-month research stay. So I went to Innsbruck to see Professor Magauer in person. I met the team and had a tour of the labs, which are state-of-the-art. And the two of us hit it off on a personal level too. He may be young, but he is already at the top of his field, certainly in Europe, if not globally. I hope to learn as much as I can from him.
How did you go about choosing your project?
My motivation was to attempt a total synthesis. I was looking for a complex molecule that is found in nature and that might be useful, but that cannot be obtained in sufficient quantities from natural sources. Since antibiotic resistance is becoming an increasingly serious problem, I chose the antibiotic known as kibdelomycin. In addition, this antibiotic is unique because it has a different mechanism of action to all others known to date, so it might be effective against resistant strains of bacteria. I really like the connection of organic synthesis with biology and its potential application in the real world.
How does a new antibiotic come to be discovered?
Pharmaceutical companies have large libraries of natural substances produced by various organisms, and they randomly test each substance and evaluate its biological properties, such as its antibiotic action. If they get good results and these substances cannot be isolated in sufficient quantities from nature, then synthesising them in the laboratory is the next thing to try. The natural world is a vast and almost inexhaustible source of biologically active substances.
What is total synthesis?
It’s like a jigsaw puzzle where what we have is a very complex molecule – a picture made up of pieces. When we perform a total synthesis, we need to prepare these individual pieces and then put them together in the right way to create the desired picture – a molecule.
So you plan to assemble kibdelomycin based on this “picture”?
Yes, although with molecules of such complexity we cannot be 100% sure that our proposed structure of kibdelomycin is correct, especially with regard to its stereochemistry. It may be the case that after I have succeeded in preparing the molecule according to the current picture, we find that the results of the analyses differ from those of the natural molecule. In that case, we would have to modify the structure accordingly. That is one of the possible challenges we have to be prepared for.
In the first year of the project, you are planning to prepare three parts out of five of the complete molecule. And the entire kibdelomycin molecule could be prepared within two years. How great a challenge is that?
Enormous. The molecule is really complex. But the chance that I will succeed within two years is a real one. Obviously, I also have to reckon with the possibility that not all stages will go according to plan and that the process will take longer. Total synthesis is a very tough job. You can design everything perfectly on paper, but then you can get stuck for several years on a single step. Nevertheless, what I like about it is how diverse a job this is, and how it forces you to come up with new, more creative solutions to synthesis. You can learn a lot.
With a molecule of such complexity, what are the chances of it ever becoming a commercial product?
That is a very difficult question to answer at this stage. We don’t know yet if we will manage to discover an easy and simple synthetic procedure. In an ideal world, if we determined that we only needed a specific part of the molecule for the antimicrobial effects, the entire process of synthesis would be greatly simplified. Another option is the semisynthetic path, whereby the basic molecule is created by bacteria, for example, and we then complete the few remaining steps through synthesis.
What are your plans for the future?
My dream is to have my own research group at some point and to work on my own ideas. The immediate plan is my research stay in Innsbruck, which I would ideally like to extend by one or two years. But I’ll see how things go and how it works out for the family.
What was your path to chemistry?
I took a bit of a roundabout route to chemistry. At high school I was considering journalism, among other things, but at the end of the day, biology won. It was a familiar subject for me because my father is a molecular biologist. So I studied experimental biology as my bachelor’s degree. However, during my experimental work on my bachelor’s thesis, I was already working on the organic synthesis of compounds with targeted biological activity. My bachelor’s thesis supervisor really gave me an enthusiasm for organic chemistry, patiently explaining everything to me and teaching me a lot. So, for my master’s degree, I switched my subject to major in bioorganic chemistry, and my PhD was purely organic chemistry. Now, thanks to antibiotics, I’m kind of going back to biology.
What do you enjoy about science?
I like its diversity. I enjoy discovery, doing new things, taking on new challenges. I like it that I can discover something that might have a practical application.
What do you do for fun outside of research?
I did track and field for a long time, so I really like doing sports. And I also enjoy reading, mostly fantasy and also popular science books. I am intrigued by other scientific disciplines and what they can teach us. Recently, I was very taken with a book called The Physics of Superheroes by James Kakalios. It’s a perfect combination of comics, which I love, and physics.
first began studying experimental biology at Palacký University in Olomouc, but during his bachelor’s thesis he switched his focus to organic synthesis due to his fascination with the field. He transferred to a master’s degree in bioorganic chemistry and applied for a doctoral study in the field of organic chemistry in the group of Dr. Jiří Pospíšil. He received 950,000 CZK from the Experientia Foundation for an annual internship in the group of professor Magauer at Innsbruck University in Austria, where he will study the total synthesis of the new antibiotic Kibdelomycin.