Antibiotics with new mechanism of action

The most dangerous antibiotic-resistant bacteria have one thing in common: they all have a double membrane that is difficult to penetrate. And even if antibiotic agents manage to break through this envelope, the bacteria generally pump them out again straight away. New antibiotics that can kill the pathogens without having to penetrate them could therefore be particularly effective. This is exactly what the synthetic Outer Membrane Protein Targeting Antibiotic (OMPTA) substance class that is currently under development does – as does darobactin, an active ingredient discovered in the natural environment. Both target BamA, a protein on the outer membrane of bacteria. Without BamA, the bacteria are unable to renew their membrane and die.

Bacteria no longer able to form outer membrane

​As part of a project conducted under NRP 72, researchers led by Sebastian Hiller at the Biozentrum of the University of Basel were able to elucidate in detail the mechanism of action by which OMPTA and darobactin inhibit BamA. They showed that the two substances imitate a particular three-dimensional structure which otherwise only occurs in the proteins that bacteria produce themselves as the building blocks of their outer membrane. This structure is the key needed to fit the proteins into certain points of the outer envelope from the inside. Both OMPTA and darobactin form a copy of this key, blocking the keyhole from the outside, so to speak. In other words, it is rather like locking the door, then snapping off the key. As a result, the route by which the bacteria transport their envelope building-blocks is sealed off and they die.

Related mechanisms are already known in microbiology and are used by other medicines. The binding structures they target are generally quite large – by microbiological standards, at least. However, the target used by OMPTA and darobactin is very small and impossible to identify using conventional methods. This is despite the fact that the substances themselves are bigger than most active ingredients and would fail to fit through the bacteria's entry gates.

Virtually no resistance

​As Hiller and his team have now demonstrated, this target on the outer envelope is the pathogens' Achilles heel. OMPTA and darobactin bind direct to the key "backbone" atoms of BamA. Because these atoms hold the protein together and determine its form, they cannot readily be modified, despite this being the easiest way for bacteria to develop resistance to these new substances in the foreseeable future. However, darobactin remained effective against all pathogens that Hiller and his team tested in the laboratory and with which resistance can be created artificially. Or, to return to the metaphor: the pathogens were unable to change the lock after it had been picked. Since OMPTA use the same mechanism, pathogens are likely to find it very difficult to develop resistance to this substance too.

These findings are an important step towards potential use in medicine. Using them, it will be possible to specifically improve OMPTA and darobactin and develop them into effective medicines. They could also provide a starting point for other novel active ingredients to combat the most dangerous antibiotic-resistant bacteria.

​August 2022

The molecular mechanism of outer membrane protein insertion by BamA and its role as a target for novel antibiotics