New method could lead to more efficient production of next-generation antibiotics

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An international team of researchers has developed a method to modify a class of antibiotics, using microscopic organisms that produce these compounds naturally.

The findings, published July 25 in Nature Chemistry, could lead to more efficient production of antibiotics effective against drug-resistant bacteria.

The team started with a microorganism genetically programmed to produce the antibiotic erythromycin. Scientists of the Institute of Organic and Chemical Chemistry Biology from Germany’s Goethe University wondered if the system could be genetically engineered to assemble the antibiotic with an extra fluorine atom, which can often improve pharmaceutical properties.

We had been analyzing fatty acid synthesis for several years when we identified part of a mouse protein that we believe could be used for the directed biosynthesis of these modified antibiotics, if added to a biological system that can already make the native compound.


Martin Grininger, Professor of Biomolecular Chemistry, Goethe University

In collaboration with David Sherman’s laboratory at the University of Michigan, which specializes in this biological assembly system, the team used protein engineering to replace part of the system’s native machinery with the mouse gene functionally similar.

“It’s like taking an engine part out of a Mercedes and putting it in a Porsche to make it a better hybrid engine. You get a Porsche engine that can do new things and performs even better,” said Sherman, a faculty member at the UM Life Sciences Institute and a professor of medicinal chemistry at the College of Pharmacy.

“We can now take advantage of this protein engineering to make new compounds containing this very desirable fluorine atom, which chemists have struggled to add to macrolide antibiotics for a long time.”

The reason this added fluorine atom is so desirable is that it not only changes the structure of the final product, but also the product’s ability to kill bacteria and work safely in patients.

Erythromycin works by binding and blocking the activity of the bacterial ribosome, which is essential for the survival of bacteria. Some bacteria have evolved ways to prevent this binding, making them resistant to treatment with antibiotics. Modifying the antibiotic’s structure with a fluorine atom overcomes this evolutionary advantage, restoring the compound’s ability to fight bacteria.

While chemists have developed methods to add fluorine synthetically, the process is arduous and requires the use of toxic chemical reagents. The new biosynthesis method developed by Goethe University and UM researchers overcomes these challenges.

“This is a very exciting development because we can bypass all the time-consuming synthetic steps and dangerous chemicals,” Sherman said. “We showed that we could essentially reprogram an organism to make the fluorinated product directly.”

The researchers point out that fluorinated compounds are still a few years away from being clinically available. But the findings offer a more efficient route to developing new antibiotics, and even antivirals and cancer drugs.

“Our approach has been proven on a small set of antibiotics, but could ultimately be used to develop a wide range of pharmaceuticals with minimal use of chemicals and toxic byproducts,” Grininger said.

This research was supported by the Volkswagen Foundation, the LOEWE program of the Land of Hesse and the National Institutes of Health.

The other authors of the study are: Alexander Rittner, Mirko Joppe, Lara Maria Mayer, Simon Reiners, Elia Heid and Dietmar Herzberg of the Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Germany; and Jennifer Schmidt of the University of Michigan Life Sciences Institute.

Source:

Journal reference:

Rittner, A., et al. (2022) Chemoenzymatic synthesis of fluorinated polyketides. Natural chemistry. doi.org/10.1038/s41557-022-00996-z.

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