Most antibiotics need to penetrate bacteria to kill them. Darobactin, a recently discovered compound, is too large for this. However, it kills many antibiotic-resistant pathogens by exploiting a tiny weak spot on their surface. Researchers in Switzerland have used this mechanism to create mimic antibiotics.
An increasing number of bacterial pathogens are resistant to antibiotics. The most dangerous of them have a common feature: a double membrane that is difficult to penetrate. Even when the antibiotics do it, the bacteria just throw them back. But a newly discovered compound called darobactin manages to bypass these protective measures and kill almost all problematic pathogens. It is a short peptide of seven amino acids, synthesized on ribosomes like normal cellular proteins.
Now researchers have been able to figure out the mechanism of its action. Its shape mimics a special three-dimensional structure. It is usually only found in proteins produced by bacteria as building blocks for their outer membrane. The structure is the “key” for inserting proteins into the outer shell at specific locations. Darobactin is a copy of this key. However, it cannot penetrate bacteria, but simply blocks the “keyhole” from the outside. As a result, the transport of the components of the bacterial membrane is impeded, and they die.
Similar mechanisms are already known in microbiology and are used by other drugs. However, darobactin is larger than most drugs and cannot pass through the entry ports of bacteria.
It turned out that in bacteria, a mutation in the BamA protein gene is responsible for the formation of the outer membrane. Darobactin attacks the “Achilles heel” of pathogens. It binds directly to the most important part of the protein, the so-called backbone atoms. Because these atoms hold the protein together and determine its shape, it is almost impossible to change them (change is just the usual way for bacteria to ward off a new antibiotic. In fact, darobactin retained its effectiveness against all pathogens for which Hiller and his team conducted laboratory tests to mimic resistance. In other words, the pathogens failed to change the “broken lock”.