Goethe University: Antibiotics from natural substances; new biosynthesis process developed | India Education | Latest Education News | World Education News

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Modification of active ingredients with the element fluorine is an important tool in modern drug development. Today, for the first time, Goethe University Frankfurt has successfully fluoridated a natural antibiotic through targeted bioengineering. With the help of this process, a whole class of medically relevant natural products can be modified – and thus promises great potential for the production of new antibiotics against resistant germs and for the (future) development of other drugs. The start-up kez.biosolutions GmbH will apply the research results.

Medical agents have been chemically modified with fluoride for decades. Because fluoride 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 length of time it stays in the body. Almost half of the drugs with small molecules of active substance (up to about 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 turn natural products into drugs is to modify them with one or more fluorine atoms. In the case of the antibiotic erythromycin, the fixed fluorine brings decisive advantages: the new erythromycin is more easily available in the body and is more effective against germs which 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, explains Martin Grininger, professor of organic chemistry and chemical biology at Goethe University. . “This means, for example, that when choosing the post

A German-American scientific team led by Professor Martin Grininger has just succeeded in exploiting the biosynthesis of a bacterium that produces antibiotics. Here, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of a macrolide antibiotic. “We introduce the fluorine unit during the manufacturing process, which is efficient and elegant,” Grininger points out, “because it allows the fluorine to be positioned very flexibly in the natural substance, which can influence its effectiveness.”

The team led by Frankfurt project leader Dr Alexander Rittner and Dr Mirko Joppe of 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 fatty acid synthase isn’t particularly picky when it comes to processing precursors, which are also important for antibiotic production in bacteria. Using clever protein design, the team managed to integrate part of the mouse enzyme into the corresponding antibiotic biosynthetic pathway. Rittner: “What is exciting is that with erythromycin we were able to fluoride a representative of an extremely broad class of substances, the so-called polyketides. About 10,000 polyketides are known and many are used as natural medicines such as antibiotics, immunosuppressants or anti-cancer drugs. Our new process therefore has enormous potential for the chemical optimization of this group of natural substances – in the case of antibiotics, above all, by overcoming resistance. In order to take advantage of this potential, Dr. Alexander Rittner the start-up kez.biosolutions GmbH.

Prof. Martin Grininger has been studying 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 start: we are already working on testing the antibiotic effect of various fluorinated compounds of erythromycin and other fluorinated polyketides and will extend the new technology to other fluorinated motifs. We will also continue the fruitful collaboration with Professor 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. In this context, Dr. Mirko Joppe also sees his work as a social mission. “Antibiotic research is not economically lucrative for various reasons. It is therefore up to universities to fill this void to develop new antibiotics in collaboration with pharmaceutical laboratories. Our technology can quickly and easily generate new antibiotics and now offers ideal starting points for projects with industrial partners.”

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