Against resistant germs: Researchers are developing a new antibiotic

Hope against “super germs”: A substance found in insects has provided the template for a new, highly effective class of antibiotics. These interrupt an important transport chain in the cell membrane of gram-negative bacteria – and thereby kill even multi-resistant pathogens. In initial tests with mice, the new antibiotics were also effective against dangerous hospital germs such as Klebsiella pneumoniae and mutated Escherichia coli. They open up new opportunities to fight infections with multi-resistant germs.

More than five million people die every year from multi-resistant germs

Antibiotics are medicine’s most important weapons against bacterial pathogens, but these are increasingly proving to be resistant. In the worst case, none of the usual remedies are effective for such infections. As a result, according to the World Health Organization WHIO, more than five million people die every year from multi-resistant pathogens. In addition to the notorious hospital germ MRSA, Gram-negative resistant bacteria such as Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa are considered to be a particular threat.

The development of new antibacterial drugs is all the more urgent. “Unfortunately, the pipeline for new antibiotics is pretty empty,” says senior author Oliver Zerbe from the University of Zurich. “No antibiotics against hitherto unused target molecules have been approved for more than fifty years.”

Hope thanks to new class of antibiotics

A newly developed class of antibiotics is now giving new hope. The starting point for this is a natural substance isolated from insects, the peptide thanatin. This molecule is found, for example, in the gut of the assassin bug Podisus maculiventris and has a naturally antibacterial effect. A few years ago, analyzes showed that thanatin interrupts an important transport chain between the inner and outer membrane of gram-negative bacteria. As a result, these metabolic products build up inside the cell and the bacterium dies.

However, Thanatin in its natural form is not suitable as an antibiotic – partly because it is too weak and resistance to it quickly develops. In order to increase the effectiveness of this active substance, Zerbe, first author Matthias Schusser and their team have now examined more closely at which point in the transport chain thanatin starts and how. The team then used this information to modify some of thanatin’s amino acid chains in such a way that its antibacterial effect is enhanced and the development of resistance is prevented.

Effective even against resistant lung infections

The researchers then tested how well the different variants of the modified thanatin worked in mice infected with Klebsiella pneumoniae or resistant forms of the intestinal germ Escherichia coli. The result: “The novel antibiotics proved to be very effective, especially in lung infections,” reports Zerbe. “In particular, they are highly effective against carbapenem-resistant enterobacteria, against which almost all available antibiotics are powerless.”

When selecting the most promising active ingredients, the researchers also found that they are also effective against bacteria that have already developed resistance to the natural thanatin. The modified variants are also designed in such a way that it is very difficult for the bacteria to form new resistances to this type of attack. “We are confident that this will significantly slow down the development of future resistances,” says Zerbe.

Prospects for a new class of antibiotics

As the study showed, the active ingredients are also non-toxic, did not damage the mice’s kidneys and remained stable in the blood over a long period of time – all properties that are a prerequisite for approval as a drug. However, further tests are now necessary before the first tests in humans can begin, as the scientists emphasize. Nevertheless, they are confident that these thanatin derivatives could become an effective weapon against gram-negative pathogens.

“Now there is a prospect that a new class of antibiotics will soon come onto the market that is also effective against resistant bacteria,” says Zerbe. (Science Advances, 2023; doi:10.1126/sciadv.adg3683)

Source: University of Zurich

Von Nadja Podbregar