2023-06-06 16:19:54
Health professionals urgently need new antibiotics to fight resistant bacteria. Researchers from the University of Zurich and the company Spexis have now modified the chemical structure of natural peptides to develop antimicrobial molecules that bind to new targets in the metabolism of bacteria.
Every year, more than five million people around the world die from bacteria resistant to the most common antibiotics. New antibiotics are urgently needed to ensure that bacterial infections in patients can still be successfully treated. “Unfortunately, the development pipeline for new antibiotics is quite empty,” says chemist Oliver Zerbe, head of NMR facilities at the University of Zurich. “It has been more than 50 years since the last antibiotics against previously unused target molecules were approved.”
In a study recently published in Scientists progress, Zerbe is now discussing the development of a class of highly effective antibiotics that fight Gram-negative bacteria in a new way. The WHO classifies this group of bacteria as extremely dangerous. The group, whose resistance is particularly high due to their double cell membrane, includes, for example, carbapenem-resistant Enterobacteriaceae. In addition to the UZH team, researchers from the pharmaceutical company Spexis AG also participated in the study as part of a collaboration co-funded by Innosuisse.
Chemically optimized natural peptide
The starting point for the researchers’ study was a natural peptide called thanatin, which insects use to ward off infections. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membranes of Gram-negative bacteria, as a study by retired UZH professor John Robinson revealed a few years ago. As a result, these metabolites accumulate inside the cells and the bacteria perish. However, thanatin is not suitable as an antibiotic, among other things because of its low effectiveness and because bacteria quickly become resistant to it.
The researchers therefore modified the chemical structure of thanatin to improve the characteristics of the peptide. “To do this, structural analyzes were essential,” says Zerbe. His team synthetically assembled the various components of the bacterial transport bridge, then used nuclear magnetic resonance (NMR) to visualize where and how thanatin binds and disrupts the transport bridge. Using this information, researchers at Spexis AG planned the chemical modifications needed to enhance the antibacterial effects of the peptide. Other mutations were made to increase the stability of the molecule, among other things.
Efficient, safe and insensitive to resistance
The synthetic peptides were then tested on mice with bacterial infections and showed exceptional results. “The new antibiotics have proven to be very effective, especially in treating lung infections,” says Zerbe. “They are also very effective against carbapenem-resistant Enterobacteriaceae, where most other antibiotics fail.” Additionally, the newly developed peptides are neither toxic nor harmful to the kidneys, and they have also been shown to be stable in the blood over a longer period of time – all properties needed to gain approval as a drug. However, further preclinical studies are needed before the first human tests can begin.
When choosing the most promising peptides for their study, the researchers made sure that they would also be effective against bacteria that had already developed resistance to thanatin. “We are confident that this will significantly slow the development of antibacterial resistance,” says Zerbe. “We now have the prospect of the availability of a new class of antibiotics that is also effective against resistant bacteria.”
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