New active substance perforates the bacterial membrane and blocks vital enzyme – double attack prevents the development of resistance
Multi-resistant forms of gonococci (Neisseria gonorrhoeae) can also be killed by Irresistin-16.
© Illustration by Alissa Eckert / CDC / Antibiotic Resistance Coordination and Strategy Unit, https://phil.cdc.gov/Details.aspx?pid=23244
– Princeton (USA) –
Like a poison arrow that penetrates the body and then releases a deadly substance: This is how the effect of a new type of antibiotic can be described. It punctures the outer membrane of bacteria and blocks a vital metabolic reaction inside. The double effect prevents the microbes from developing protective mechanisms and becoming resistant, as American molecular biologists report in the journal “Cell”. The active ingredient is able to kill both gram-positive bacteria such as staphylococci and enterococci as well as gram-negative bacteria such as E. coli and Neisseries. In animal experiments, the antibiotic also eliminated pathogens that had become resistant to all currently available antibiotics. There are no clinical studies yet.
“It’s the first antibiotic that works against gram-positive and gram-negative bacteria without creating resistance,” says Zemer Gitai from Princeton University. His working group looked for around 33,000 chemical substances for antibiotic compounds that can be used against infectious agents from both large groups of bacteria. An active ingredient that was later called chemical resist after a chemical change proved to be particularly promising. Because all attempts to create resistant germs failed. Only after extensive analysis did the researchers discover how the unusual antibiotic unfolds its deadly effect: part of the molecule destroys the membrane structure, another part of the same molecule inhibits an enzyme that is necessary for the production of folic acid (folate). Folic acid, for example, is essential for the formation of the nucleic acids DNA and RNA.
There are already antibiotics that attack the membrane of bacteria and those that inhibit their folic acid formation. However, even when given in combination, they were not as effective as Irresistin, which the researchers explain with a synergistic effect. In general, it may be more advantageous to use a compound with two mechanisms of action rather than two compounds with one effect each. Irresistin prevented the growth of gonococci (Neisseria gonorrhoeae), Acinetobacter baumannii – a hospital bacterium, enterococci and multi-resistant staphylococci (MRSA) in laboratory cultures.
However, the starting substance had the disadvantage of also damaging human cells. However, chemical optimization has succeeded in producing a molecule variant called irresistin-16, which was more than a hundred times more effective against bacteria than against human cells, so that the active ingredient could be administered in low doses. The researchers successfully used Irresistin-16 in mice infected with highly resistant gonococci without causing severe side effects. This is an important finding for the further development of urgently needed new antibiotics, says Gitai. Perhaps other active substances that attack both bacteria and human cells in their original form could also be chemically modified so that therapeutic use is possible.
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