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Promising antibiotic discovered
For a long time, antibiotics were regarded as a miracle weapon against bacterial infections. However, many pathogens have adapted to the active ingredients and have become resistant, which is why the search for new antibacterial substances is becoming increasingly important. An international research team involving the University of Basel has now discovered a new antibiotic using computer analyses and deciphered its mode of action. Their study may contribute to the development of new effective drugs.
10/11/2022
The WHO refers to the creeping and rapidly growing number of antibiotic-resistant bacteria as the «silent pandemic». This is exacerbated by the fact that hardly any new drugs have come onto the market in recent decades. Even today, not all infections can be treated. New active substances are urgently needed to halt the advance of antibiotic-resistant germs. The team led by Prof Dr Sebastian Hiller from the Biozentrum of the University of Basel and researchers from Northeastern University in Boston have now discovered another active substance. The work was carried out as part of the National Centre of Competence in Research (NCCR) «AntiResist» and has now been published in «Nature Microbiology».
The researchers discovered the antibiotic dynobactin through computer-based screening. It kills gram-negative bacteria, which include many dangerous and resistant germs. «Finding antibiotics against this group of bacteria is anything but trivial», says Hiller. «They are well protected by their double membrane and therefore offer few opportunities for attack. And in the millions of years of their evolution, they have found numerous ways to render antibiotics harmless.»
It was only last year that Hiller's team deciphered the active principle of the recently discovered peptide antibiotic darobactin. These findings fed directly into the search for new antibiotics. Among other things, the researchers took advantage of the fact that many bacteria produce antibiotic peptides themselves in order to fight each other. And that these peptides, in contrast to natural substances, are fixed in the genetic material of the bacteria.
«The genes for such peptide antibiotics have a clear distinguishing mark», explains co-first author Dr Seyed M. Modaresi. «The computer systematically searched the entire genome of bacteria that produce such peptides for this characteristic. In the process, we came across dynobactin.» The authors were able to show in their study that it is effective. Mäuse with life-threatening septicaemia caused by resistant bacteria survived the severe infection by administering Dynobactin.Mode of action investigated
Through a combination of different methods, the researchers were able to determine the structure and mode of action of dynobactin. It blocks the bacterial membrane protein BamA, which plays an important role in the formation and renewal of the germs' outer protective shells. Dynobactin is stuck in BamA from the outside like a cork and prevents it from fulfilling its tasks. The bacteria die», says Modaresi. «Although Dynobactin has hardly any chemical similarities with the well-known Darobactin, it gets hold of the bacteria in the same place. We did not expect this at the beginning.
On a molecular level, however, the researchers discovered that Dynobactin interacts differently with BamA than Darobactin. By combining certain properties of the two, the potential active substances could be further improved and optimised. This is an important step on the way to an effective drug. «The computer-based screening method will give a new boost to the search for urgently needed antibiotics», says Hiller. «In the future, we want to expand the whole thing and test even more peptides for their suitability.»
Source: LABO from 10 November 2022
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