More and more bacterial pathogens are developing antibiotic resistance. Typical hospital germs such as E. coli and K. pneumoniae have become resistant to most—or in some cases, all—currently available antibiotics. These bacteria are especially difficult to attack because they have an additional external membrane that prevents many substances from getting into the cell interior.
According to the World Health Organization, the need for research and development against antibiotic-resistant pathogens is at an all-time high. We’re at a lack of new active substances, especially for the treatment of diseases caused by the so-called gram-negative bacteria like those mentioned above. But in a study published yesterday in Nature, researchers discovered a novel peptide that attacks gram-negative bacteria at a previously unknown site of action.
“Since the 1960s, scientists have not succeeded in developing a new class of antibiotics effective against gram-negative bacteria,” coauthor Till Schäberle of JLU says, “but this could now be possible with the help of this peptide.”
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The researchers tested extracts of bacterial symbionts of insect-pathogenic nematodes to verify their activity against E. coli. In this way, they were able to isolate a peptide that they called Darobactin. Darobactin consists of seven amino acids and shows structural characteristics. Several of its amino acids are linked via unusual ring closures. This substance also shows no cell toxicity—a prerequisite for its use as an antibiotic.
“We have already been able to gain insights about how the bacteria synthesize this molecule,” Schäberle says. “Currently we are working in the field of natural product research at the Institute of Insect Biotechnology of the JLU to increase the production of this substance and to generate analogues.”
The researchers also determined the site of action of Darobactin. They found that Darobactin binds to the BamA protein, located in the external membrane of gram-negative bacteria. As a result, the establishment of a functional external membrane is disrupted and the bacteria die off. “It is particularly interesting to note that this previously unknown weak point is located on the outside of the bacteria where substances can easily reach it,” Schäberle adds.
Darobactin exhibited an encouraging effect on infections with both wild-type and antibiotic-resistant P. aeruginosa, E. coli, and K. pneumoniae strains. Thus, Darobactin is a very promising new substance that could be used to develop a new antibiotic.
Image: Multidrug-resistant E. coli bacteria. Image courtesy of Justus Liebig University Giessen/Katrina Friese.