Drug design: Making sugar molecules aggressive

Breaking down bacterial biofilms in order to lure the pathogens out of hiding is one of chemist Dr Alexander Titz’s goals. The junior research group leader from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) develops substances that target this bacterial protective wall. His most promising candidates include chemically modified sugar molecules. We wanted to find out more and paid the DZIF researcher a visit in the newly constructed HIPS building.

Alexander Titz

Alexander Titz

“Drug design and optimisation” is written on his door; meaning research between the disciplines. Titz’s research project topics make this clear: one of them is “Chemical biology of carbohydrates”, and another “Medicinal chemistry of natural products”. Does he cross borders? “I am a chemist,” the scientist explains, and after a short pause admits: “and meanwhile maybe with a touch of biology.”

Alexander Titz aced his studies in chemistry at the TU Darmstadt in 2004. At that point, he had already taken his first step towards medicine with his diploma thesis which he prepared at Novartis Pharma AG in Switzerland. He returned to university for his PhD, but continued living in Switzerland; a position in Basel interested him, at the Institute of Molecular Pharmacology, where he worked with protein and carbohydrate interactions, sugars, so to say.

“Since then my work has revolved around topics in the sugar community,” says Titz. He himself seems to find it surprising how coincidences sometimes determine paths, because sugar molecules are still at the centre of his research activities today, and Switzerland became his home country for a longer period of time. “I lived there for nine years,” he says. And mountain climbing was only one of the many sports he enjoyed during his PhD. In 2008, after completing his PhD with distinction, he changed to the ETH Zürich (Swiss Federal Institute of Technology) and conducted research in the field of molecular biology and microbiology. He was awarded the Klaus-Grohe Prize for medicinal chemistry for his work on protein-carbohydrate interactions.

In 2009, Alexander Titz’s life was disrupted by a serious accident and he has been in a wheelchair ever since. The tragic incident demanded a lot of strength and willpower from the young scientist to continue on his path. However, after spending only half a year in a rehabilitation clinic, he continued his research career; the tragedy is hardly noticeable in his curriculum vitae. In 2010, the scientist changed to the Zukunftskolleg of the University of Constance, where, in a project, he brought together his previous research in microbiology and on medical questions. “Given the circumstances, I was lucky, because I am still able to do good research work.” Which is an understatement: with a team of currently six people Alexander Titz presents promising solutions in the fight against bacteria.

Teamwork (from left to right): Dr. Matthew Calvert, Dr. Stefanie Wagner, Ghamdan Beshr, Roman Sommer, Ines Joachim, Dirk Hauck, Dr. Alexander Titz

Teamwork (from left to right): Dr. Matthew Calvert, Dr. Stefanie Wagner, Ghamdan Beshr, Roman Sommer, Ines Joachim, Dirk Hauck, Dr. Alexander Titz

Alexander Titz team’s strategy is to target this biofilm and break it down as far as possible. Targets for this include lectins which are produced by the bacteria and act as adhesives in the biofilm. At several sites, they bind to sugar molecules such as mannose and galactose and connect them with both the bacteria and the host cells. The researchers now want to use these sugar molecules and chemically manipulate them to turn them into lectin inhibitors. “We modify the sugar molecules so that they can very specifically bind to lectins and displace the unmodified sugar molecules,” Titz explains. The sticky substance should then break down, and expose the bacteria to drugs. There is also a chance that these molecules will not cause resistance. They do not kill the bacteria and consequently do not expose them to selection pressure, as would be the case with antibiotics.

The young researcher has already registered two patents for lectin inhibitors, and a small company is interested in jointly developing them further. A DZIF research group is also searching for lectin inhibitors. Here, Titz concentrates more on natural substances and modifying them. The DZIF Natural Compound Library offers a large range of potential inhibitors. And Titz appreciates this nationwide network: “It is good that the DZIF is helping to bridge the gap between industry and research, two ivory towers.”

Breaking down biofilms is one thing. Alongside this, Alexander Titz and his team are also working on developing new antibiotics and, as much as possible, the kind which do not immediately cause resistance. The natural substance argyrin seems to be a good candidate, but, first and foremost, it is also poisonous. “With sugars, the work is about virtually making them ‘more aggressive’ or ‘more willing to bond’. With argyrin the opposite is the case,” explains Titz. “Here, we need to ensure that the antibiotic effect does not affect everything.” However, according to the chemist, “Even here we will find ways of manipulating it.”

The newly constructed HIPS building provides optimal conditions for his research. The entire second floor is available to his “drug design and optimisation”: from synthesis to analysis, all the way through to bioactivity measurement. It even has a biosafety level 2 laboratory for investigating dangerous pathogens. Ideal prerequisites for optimising aggressive sugars and other novel active substances.  

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