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.
Journal Reference:
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/)