Health professionals urgently need new antibiotics to tackle resistant bacteria.
Researchers at the University of Zurich (UZH), in Switzerland, and the company Spexis, have now modified the chemical structure of natural peptides to develop antimicrobial molecules that bind to new targets in bacterial metabolism.
Every year, more than five million people worldwide die from bacteria resistant to the most common antibiotics. New antibiotics are urgently needed to ensure that bacterial infections in patients can still be treated successfully.
“Unfortunately, the development pathway for new antibiotics is quite empty,” said chemist Oliver Zerbe, head of the NMR facility at the University of Zurich.
“It has been more than 50 years since the last antibiotic against a previously unused target molecule was approved.”
In a study recently published in Science Advances, Zerbe discusses developing a class of highly effective antibiotics that fight Gram-negative bacteria in novel ways. WHO classifies this group of bacteria as very dangerous. The group, whose resistance is very high because of their dual cell membranes, includes carbapenem-resistant enterobacteria, for example. In addition to the UZH team, researchers from the pharmaceutical company Spexis AG were also involved in this study as part of a collaboration co-funded by Innosuisse.
Chemically optimized natural peptides
The starting point for the research was a natural peptide called thanatin, which insects use to fend off infection. Thanatin interferes with the important lipopolysaccharide transport bridge between the outer and inner membranes of Gram-negative bacteria, as was revealed several years ago in a study conducted by retired UZH professor John Robinson. As a result, these metabolites accumulate in the cell, and the bacteria die. However, thanatin is not suitable for use as an antibiotic drug, partly because of its low effectiveness and because bacteria quickly become resistant to it.
Therefore, researchers modified the chemical structure of thanatin to improve the characteristics of the peptide.
“To do this, structural analysis is essential,” said Zerbe.
His team synthetically assembled various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualize where and how thanatin binds to and disrupts the transport bridge. Using this information, the Spexis researchers planned the chemical modifications needed to enhance the peptide’s antibacterial effect. Further mutations are carried out to increase the stability of the molecule, among other things.
Effective, safe and immune to resistance
The synthetic peptide was then tested on mice with a bacterial infection – and produced amazing results.
“New antibiotics are proving very effective, especially for treating lung infections,” said Zerbe.
“They are also very effective against carbapenem-resistant enterobacteria, where most other antibiotics fail.”
In addition, the newly developed peptides are not toxic or harmful to the kidneys, and they are also shown to be stable in the blood over a longer period of time – all properties necessary for approval as drugs. However, further preclinical studies are needed before the first tests in humans can begin.
When selecting the most promising peptides for their study, the researchers ensured that they would also be effective against bacteria that had developed resistance to thanatin.
“We believe this will significantly slow down the development of antibacterial resistance,” said Zerbe.
“We now have the prospect of a new class of antibiotics becoming available that are also effective against resistant bacteria.”
Learn more about the development of antimicrobial peptides as new antimicrobial agents in our recent in-depth article on the subject.