Focusing on protein-protein interactions
Using state-of-the-art methods, the Zurich researchers succeeded in proving that thanatin disrupts the transport of LPS molecules to the outer membrane.The transport pathway consists of a super-structure of seven different proteins that assemble to form a bridge from the inner membrane across the periplasmic space to the outer membrane. LPS molecules cross this bridge to the cell’s surface, where they form part of the structure of the outer membrane. Thanatin is able to block the protein-protein interactions that are needed to form the bridge. As a result, LPS molecules are prevented from reaching their destination and the biogenesis of the entire outer membrane is inhibited – which is fatal for the bacteria.
New potential clinical candidates
“This is an unprecedented mechanism of action for an antibiotic and immediately suggests ways to develop new molecules as antibiotics targeting dangerous pathogens,” explains Robinson. “This finding shows us a way to develop substances that specifically inhibit protein-protein interactions in bacterial cells.”
Stefan U. Vetterli, Katja Zerbe, Maik Müller, Matthias Urfer, Milon Mondal, Shuang-Yan Wang, Kerstin Moehle, Oliver Zerbe, Alessandra Vitale, Gabriella Pessi, Leo Eberl, Bernd Wollscheid, and John A. Robinson. Science Advances, 2018, 16 November. DOI: 10.1126/sciadv.aau2634