Peptide modified to fight resistant bacteria

Health professionals are in urgent need of new antibiotics to tackle resistant bacteria. Researchers at the University of Zurich (UZH) and pharmaceutical company Spexis have now modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria’s metabolism.

New antibiotics are urgently needed to ensure that bacterial infections in patients can still be treated successfully. As noted by UZH chemist Oliver Zerbe, “Unfortunately, the development pipeline for new antibiotics is fairly empty; it’s been more than 50 years since the last antibiotics against previously unused target molecules were approved.”

In a study recently published in the journal Science Advances, Zerbe now discusses the development of a highly effective class of antibiotics that fight gram-negative bacteria — classified by the WHO as extremely dangerous — in a novel way. Researchers from Spexis were also involved in the study as part of a collaboration co-funded by Innosuisse.

The starting point for study was a naturally occurring peptide called thanatin, which insects use to fend off infections. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membrane of gram-negative bacteria, as revealed a few years ago in a study by now retired UZH professor John Robinson. As a result, these metabolites build up inside the cells and the bacteria perish.

Thanatin unfortunately isn’t suitable for use as an antibiotic drug, among other things due to its low effectiveness and because bacteria quickly become resistant to it. The researchers therefore modified the chemical structure of thanatin to enhance the peptide’s characteristics.

“To do this, structural analyses were essential,” Zerbe said. His team synthetically assembled the various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualise where and how thanatin binds to and disrupts the transport bridge. Using this information, researchers from Spexis planned the chemical modifications that were necessary to boost the peptide’s antibacterial effects. Further mutations were made to increase the molecule’s stability, among other things. The synthetic peptides were then tested in mice with bacterial infections — and yielded outstanding results.

“The novel antibiotics proved very effective, especially for treating lung infections,” Zerbe said. “They are also highly effective against carbapenem-resistant enterobacteria, where most other antibiotics fail.”

In addition, the newly developed peptides aren’t toxic or harmful to the kidneys, and they also proved stable in the blood over a longer period — all of which are properties that are required for gaining approval as a drug. However, further preclinical studies are needed before the first tests in humans can begin.

When choosing the most promising peptides for their study, the researchers made sure that they would also be effective against bacteria that have already developed resistance to thanatin. According to Zerbe, this should significantly slow down the development of antibacterial resistance.

“We now have the prospect of a new class of antibiotics becoming available that is also effective against resistant bacteria,” he said.

Image credit: iStock.com/Manjurul