New method against antibiotic resistance more effective?

Possible approach to the treatment of multi-resistant germs discovered
Antibiotic-resistant bacterial strains are a growing problem worldwide. Conventional drug treatments with antibiotics are losing their effectiveness and previously well-controllable diseases suddenly represent a serious health risk. Scientists at the Ludwig Maximillians University (LMU) in Munich now have together with colleagues from the USA discovered a possible alternative to conventional antibiotics, which should also have an effect on multi-resistant germs.

"Multi-resistant bacteria, in which antibiotics are no longer effective, are an increasing problem in medicine," according to the LMU. However, antibiotics from the group of so-called orthosomycins could help here. According to the LMU, these start at a completely different binding site in bacteria than the other antibiotics. The research team around Dr. Daniel Wilson from the LMU gene center, Dr. Scott Blanchard from Cornell University (USA) and Dr. In a recent study, Yury Polikanov from the University of Illinois at Chicago (USA) structurally characterized two orthosomycins and revealed their mode of action. The scientists published their results in the journal "Proceedings of the National Academy of Sciences" (PNAS).

New antibacterial drugs urgently needed
In view of the increasing resistance to antibiotics and the associated difficulties in treatment, the development of new antibacterial drugs is urgently required. "Biochemical studies indicate that so-called orthosomycin antibiotics could be an effective alternative," report the LMU scientists. According to the researchers, the orthosomycins differ structurally from other antibiotics. In comparison, their molecules are very elongated. "Like most antibiotics, orthosomycins dock onto the bacterial protein factories - the ribosomes" and "there they prevent the production of new proteins that are necessary for the survival and multiplication of the pathogens," the LMU said. However, they apparently use a different docking site for the ribosomes than the other antibiotics.

Hitherto unknown binding site discovered
"For two of these orthosomycins, evernimicin and avilamycin, we have now used high-resolution cryo-electron microscopic images to determine exactly where they bind," explains study author Stefan Arenz from the LMU. The researchers were able to demonstrate that these antibiotics dock at a previously unknown binding site in the ribosome. According to the scientists, the newly discovered binding site lies in a specific turn of the ribosome and enables evernimicin and avilamycin to bind to both ribosomal RNA and ribosomal protein at the same time. This is "a completely different binding site than with other antibiotics", which is why "no cross-resistance to other antibiotics" occurs, reports Stefan Arenz.

Blocked production of proteins
With the help of additional fluorescence resonance energy transfer (FRET) analyzes, the scientists were also able to explain how the orthosomycins paralyzed the ribosome and prevented the multiplication of the bacteria. In order to synthesize proteins, so-called tRNA must first bind to the ribosome at one end and then “swing” at the other end into the active center of the ribosome, the scientists explain. Evernimicin and avilamycin block this swinging in because they are spatially in the way of the tRNA, continues Arenz. In this way, protein production in the ribosome is shut down. The researchers hope that the current findings could help to develop better active substances against multi-resistant germs in the future. (fp)

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