Scientists develop new class of antibiotics to fight resistant bacteria

Bacteria

Researchers from the University of Zurich and Spexis have reengineered the chemical structure of a natural peptide, tanatin, to develop a new class of antibiotics that can fight resistant bacteria. Synthetic peptides have demonstrated efficacy, safety and resistance to bacterial immunity in tests on mice, offering the potential for a new type of antibiotic that can fight resistant strains.

There is a pressing demand for new antibiotics among health experts to fight resistant bacteria. A team of scientists from the University of Zurich and the company Spexis have adapted the chemical structure of naturally found peptides to create antimicrobial substances that attach to new targets in bacterial metabolism.

Each year, over five million people worldwide succumb to antibiotic resistant bacteria. The development of new antibiotics is of paramount importance to ensure the successful treatment of bacterial infections in patients.

Unfortunately, the development pipeline for new antibiotics is pretty empty, says chemist Oliver Zerbe, head of NMR facilities at the University of Zurich. More than 50 years have passed since the last antibiotics against previously unused target molecules were approved.

In a study recently published inThe progress of scienceZerbe now talks about developing a highly effective class of antibiotics that fights Gram-negative bacteria in a new way. 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, the 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-financed by Innosuisse.

Chemically optimized natural peptide

The starting point for the researchers’ study was a natural peptide called tanatin, which insects use to fend off infection. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membranes of Gram-negative bacteria, as revealed a few years ago in a study by UZH professor John Robinson, now retired. As a result, these metabolites accumulate inside cells and the bacteria die. However, thanatin is not suitable for use as an antibiotic drug, among other things due to its low efficacy and because the bacteria quickly become resistant to it.

The researchers then modified the chemical structure of tanatin to improve the characteristics of the peptides. To do this, structural analyzes were essential, Zerbe says. Her team synthetically assembled the various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualize where and how tanatin binds to and disrupts the transport bridge. Using this information, researchers at Spexis AG engineered the chemical modifications needed to enhance the antibacterial effects of the peptides. Further mutations have been made to increase the stability of the molecules, among other things.

Effective, safe and immune to resistance

The synthetic peptides were then tested on mice with bacterial infections and produced outstanding results. The new antibiotics have proven very effective, especially for treating lung infections, says Zerbe. They are also highly effective against carbapenem-resistant enterobacteria, where most other antibiotics fail. Furthermore, the newly developed peptides are not toxic or harmful to the kidneys and have also been shown to be stable in the blood for a longer period, all properties necessary to gain approval as a drug. However, more 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 they were also effective against bacteria that had already developed resistance to tanatin. We are confident that this will significantly slow the development of antibacterial resistance, says Zerbe. We now have the prospect of making available a new class of antibiotics that is also effective against resistant bacteria.

Reference: Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae by Matthias Schuster, Emile Brabet, Kathryn K. Oi, Nicolas Desjonqures, Kerstin Moehle, Karen Le Poupon, Sophie Hell, Stphane Gable, Virginie Rithi, Sverine Dillinger, Peter Zbinden, Anatol Luther, Claudia Li, Sarah Stiegeler, Carolin D’Arc or, Hans Locher, Tobias Remus, Selena DiMaio, Paola Motta, Achim Wach, Franoise Jung, Grgory Upert, Daniel Obrecht, Mohammed Benghezal and Oliver Zerbe, May 24, 2023, The progress of science.
DOI: 10.1126/sciadv.adg3683


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