Mice cured of gonorrhea
New antibiotic relieves mice of gonorrhea
Vera Sysoeva, N+1
Scientists have changed the formula of a substance that blocks protein synthesis in some bacteria, and obtained an antibiotic resistant enough to be used to treat animals. To cure mice of gonorrhea, only one dose of the drug was needed, that is, the resulting substance can become an effective and convenient means in clinical use. The work was published in Nature Communications (Aron et al., trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo).
Bacteria resistant to existing antibiotics pose a great danger to humans. WHO estimates that infections caused by such resistant pathogens will be able to claim the lives of about ten million people a year by 2050, if the situation does not change. The dangerous resistant bacteria that need new antibiotics include the gonorrhea-causing Neisseria gonorrhoeae.
New antibacterial agents suggest targeting, for example, one of the mechanisms that supports normal protein synthesis in bacterial cells, but at the same time is very different from that in eukaryotic cells. Often, ribosomes, finishing the synthesis of the polypeptide chain, cannot themselves "get off" the matrix RNA and release the newly synthesized protein. In this case, bacteria have ways to separate stuck ribosomes, protein and matrix RNA, and this mechanism is not at all similar to those used in similar situations by animal cells. In addition, in some bacteria, including N.gonorrhoeae, such a mechanism is the only one, and if it is blocked, the whole process of protein production stops in cells, and the bacteria themselves die.
Previously, scientists described a group of substances (acylaminooxadiosols) that, according to this principle, reduce the viability of Escherichia coli Escherichia coli. One of the substances in this group binds to the ribosomes of Escherichia coli and Mycobacterium smegmatis, effectively blocking protein synthesis in cells.
A team of scientists from several US universities led by Christine Dunham and Kenneth Keiler decided to improve the substances of this group so that they could be used as an effective remedy against N.gonorrhoeae for the treatment of animals, including possibly humans. The fact is that the already existing substance, on which previous studies were conducted, is too unstable in animal organisms, decomposes quickly with water and does not have time to act on pathogenic bacteria. To find a suitable compound, the researchers tested more than 500 analogues of the original translation inhibitor. Scientists managed to find one substance that was stable enough and also penetrated well into the intestinal cell line, which indicated the theoretical possibility of prescribing medicine to animals orally.
A block diagram of the substance on which the researchers relied in their work (left) and the resulting substance, the effectiveness of which was tested on mice (right). A drawing from the article by Aron et al.
The compound proved to be an effective antibiotic against Gram-positive bacteria, as well as most gram-negative ones, including N.gonorrhoeae. Experiments on eukaryotic cells have shown low toxicity.
Then the scientists moved on to experiments on animal models. At first, healthy mice were prescribed either one large dose of the drug (100 milligrams per kilogram of animal weight), or several times 10 milligrams per kilogram. After making sure that healthy animals did not have any undesirable effects from taking an antibiotic, the scientists gave 10 milligrams per kilogram of the substance to mice infected with a strain of N.gonorrhoeae resistant to seven classes of antibiotics. Six days after taking the new antibiotic, 80 percent of the mice were completely cured, and the number of pathogenic bacteria in the genital tract significantly decreased in all the others.
The researchers also studied in detail the mechanism of action of the substance using cryo-electron microscopy and described how changes in one or another part of the compound affect its effectiveness. The scientists came to the conclusion that the substance they showed is very different in principle from other classes of antibiotics, which also block protein translation. The authors also note that the new antibiotic is particularly notable for the possible scheme of use – the drug requires only a single oral intake, which could be convenient for both doctors and patients, and would help reduce the risk of bacterial resistance to the new drug.
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