Goethe University: Antibiotics from natural substances; new biosynthetic process developed

The modification of active ingredients with the element fluorine is an important tool in modern drug development. Now, for the first time, the Goethe University in Frankfurt has succeeded in fluorinating a naturally occurring antibiotic through targeted bioengineering. With the help of this process, a whole class of medically relevant products from nature can be modified – and thus promises great potential for the production of new antibiotics against resistant germs and for the (further) development of other medicines. The start-up company kez.biosolutions GmbH will apply the research results.

Medical agents have been chemically modified with fluorine for decades. Because fluorine has many therapeutically useful effects: It can improve the binding of the active substance to the target molecule, make the active substance more readily available to the body and change the time it stays in the body. Almost half of the drugs with small active substance molecules (up to approx. 100 atoms) approved by the US Food and Drug Administration (FDA) now contain at least one bonded fluorine atom. These include drugs as diverse as cholesterol-lowering drugs, antidepressants and antibiotics.

Complex natural products are often produced by bacteria or fungi to gain a growth advantage. One way to develop natural products into drugs is to modify them with one or more fluorine atoms. In the case of the antibiotic erythromycin, the attached fluorine brings decisive advantages: the new erythromycin is more readily available in the body and is more effective against germs that have developed resistance to erythromycin. The synthetic-chemical processes for introducing fluorine into natural substances are very complex and often “brutal” due to the chemicals and reaction conditions required, says Martin Grininger, Professor of Organic Chemistry and Chemical Biology at Goethe University. “This means, for example, that when choosing the position

A German-American scientific team led by Prof. Martin Grininger has now succeeded in exploiting the biosynthesis of an antibiotic-producing bacterium. Here, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of a macrolide antibiotic. “We introduce the fluorinated unit during the manufacturing process, which is effective and elegant,” emphasizes Grininger, “because it allows the fluorine to be positioned very flexibly in the natural substance, which can influence its effectiveness.”

The team led by the Frankfurt project manager Dr. Alexander Rittner and Dr. Mirko Joppe from Grininger’s group inserted a subunit of the enzyme called fatty acid synthase into the bacterial protein. The enzyme naturally participates in the biosynthesis of fats and fatty acids in mice. Rittner explains that the fatty acid synthase is not particularly picky when it comes to processing the precursors, which are also important for the production of antibiotics in bacteria. Using intelligent protein design, the team succeeded in integrating part of the mouse enzyme into the corresponding biosynthetic pathway of the antibiotic. Rittner: “The exciting thing is that with erythromycin we were able to fluorinate a representative of an enormously large class of substances, the so-called polyketides. Around 10,000 polyketides are known and many are used as natural product drugs such as antibiotics, immunosuppressants, or anticancer drugs. Our new process therefore has huge potential for the chemical optimization of this group of natural substances – in the case of antibiotics, above all, overcoming resistance.” In order to leverage this potential, Dr. Alexander Rittner the start-up company kez.biosolutions GmbH.

Prof. Martin Grininger has been researching the tailor-made biosynthesis of polyketides for several years: “The successful fluorination of a macrolide antibiotic is a breakthrough for which we have done a lot and of which I am now very proud. At the same time, it is a departure: We are already working on testing the antibiotic effect of various fluorinated erythromycin compounds and other fluorinated polyketides and will expand the new technology to other fluorine motifs. We will also continue the successful collaboration with Prof. David Sherman and his team at the University of Michigan.”

The search for drugs that overcome resistance is an ongoing task because – depending on the frequency of use – it is quite normal for resistance to develop sooner or later. Against this background, Dr. Mirko Joppe also sees his work as a social mission. “Research on antibiotics is not economically lucrative for various reasons. It is therefore the task of the universities to fill this gap in order to develop new antibiotics together with pharmaceutical companies. Our technology can generate new antibiotics quickly and easily and now offers ideal starting points for projects with industrial partners”.