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

An international team of researchers has developed a way to alter one class of antibiotics, using microorganisms that naturally produce these compounds.

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 from the Institute of Organic Chemistry and Chemistry A biologist at Germany’s Goethe University wondered if the system could be genetically modified to synthesize the antibiotic with an extra fluorine atom, which could often improve pharmaceutical properties.

We’ve been analyzing fatty acid synthesis for several years when we identified a portion of a mouse protein that we thought could be used in the targeted biosynthesis of these modified antibiotics, if added to a biological system that could actually make the original compound. “

Martin Greninger, Professor of Biomolecular Chemistry, Goethe University

Working with David Sherman’s lab at the University of Michigan, who specializes in this biological assembly system, the team used protein engineering to replace one part of the system’s original machinery with a functionally similar mouse gene.

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

“We can now leverage this protein engineering to make new compounds with the highly desirable fluorine atom, which chemists have been struggling to add to macrolide antibiotics for so long.”

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

Erythromycin works by binding to the bacterial ribosome and blocking its activity, which is essential for survival. Some bacteria have developed ways to block this association, making them resistant to antibiotic treatment. Changing the antibiotic’s structure with a fluorine atom overrides that evolutionary advantage, restoring the compound’s ability to fight bacteria.

While chemists have developed methods for artificially adding fluorine, the process is laborious and requires the use of toxic chemical reagents. A new biosynthesis method developed by researchers from Goethe University and UM overcomes those challenges.

“It’s a very exciting development, because we can bypass all the synthetic steps and dangerous chemicals that take so long,” Sherman said. “We’ve shown that we can basically reprogram an organism to make the fluorinated product directly.”

The researchers stress that fluorinated compounds are still a few years away from being available in the clinic. But the findings offer a more effective path forward in developing new antibiotics, and even antivirals and anticancer drugs.

“Our approach has proven successful in a small group of antibiotics, but could eventually be used to develop a wide range of drugs with minimal use of chemicals and toxic by-products,” Groeninger said.

This research was supported by the Volkswagen Foundation, the LOEWE Program for the State of Hesse, and the National Institutes of Health.

The other study authors are: Alexander Rittner, Mirko Jobe, Lara Maria Mayer, Simon Reiners, Elijah Head 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.


Journal reference:

Rittner, A.; et al. (2022) Enzymatic chemical synthesis of fluorinated polyketides. Nature chemistry.

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