One of the last arrows in the quiver in the fight against dangerous bacteria is the reserve antibiotic daptomycin. It is used primarily when conventional drugs fail due to resistant bacteria. Although the antibiotic was developed around 30 years ago, its exact mode of action was previously unclear. Scientists have now deciphered the puzzle: Daptomycin blocks the integration of important building blocks into the cell wall of the pathogens, thereby killing the bacteria. The results have now been published in the journal Nature Communications.

When it comes to bacterial infections, antibiotics are the medical weapons of choice - but they are becoming increasingly blunt. The number of resistances is increasing, which is why many antibiotics are no longer effective against the dangerous pathogens. Some of these active substances are intended for particularly severe infections with resistant bacteria. One example is daptomycin, which was launched in the USA in 2003 and in Germany in 2006. It is used for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) and resistant enterococci.

"Although daptomycin was discovered around 30 years ago, the exact mode of action remained elusive until now," explains the senior author. There were different theories on how this antibiotic attacks and kills bacteria. One of them was that daptomycin perforates the bacterial envelope and leads to a potassium efflux that ends with the death of the bacterium. "Nobody understood how daptomycin actually works," says one of the lead authors.

The interdisciplinary team used a wide variety of scientific methods to discover the antibiotic's mode of action. The researchers first labelled daptomycin with a fluorescent dye that glows green. This enabled them to follow exactly where the antibiotic docks to the staphylococcal cells under the high-resolution microscope. "Daptomycin binds to the bacteria in regions where the new cell wall is just being synthesized," said another lead author.

Like in a construction kit, the bacterial cell wall is assembled from numerous building blocks. Further analyses carried out by the researchers on staphylococci and synthetically produced bacterial walls showed that two of these building blocks in particular are hugely important for the effect of daptomycin: the central cell wall building block "lipid II" and the membrane lipid phosphatidylglycerol (PG). "The combination of lipid II and PG together is the Achilles' heel of the bacteria," says the senior author. This is exactly where daptomycin comes into play: The antibiotic captures these important building blocks and blocks the further construction of the cell wall. As a result, the bacterial cell wall becomes unstable resulting in the outflow of various ions, including potassium. "The outflow of ions is not the actual killing mechanism of daptomycin, as originally thought, but a consequence of bacterial cell death," concludes the senior author.

https://www.uni-bonn.de/neues/071-2020

https://www.nature.com/articles/s41467-020-15257-1

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fca2-daptomycin-targets&filter=22