Researchers have modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria's metabolism.
The University of Zurich and the company Spexis have modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria's metabolism. This has led to a new class of antibiotics that fight Gram-negative bacteria in a novel way. This includes carbapenem-resistant enterobacteria.
The starting point for the researchers' 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 a result, these metabolites build up inside the cells, and the bacteria perish.
Antimicrobial peptides (AMPs) possess great potential for combating drug-resistant bacteria. Thanatin is a pathogen-inducible single-disulfide-bond.
However, thanatin is not 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. Here, the scientists synthetically assembled the 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, researchers from Spexis AG 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 good results, being effective against carbapenem-resistant enterobacteria.
Matthias Schuster, Emile Brabet, Kathryn K. Oi, et al. Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae. Science Advances, 2023; 9 (21) DOI: 10.1126/sciadv.adg3683
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)
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