In the power of retro: the unique effect of a "forgotten" antibiotic will help fight superbugs

For the first time, Russian scientists have described the mechanism of action of a powerful antibiotic, which has remained a mystery for more than half a century. Discovered in 1957 in Germany, bottromycin A2 proved effective against dangerous infectious agents that other drugs could not help. However, it was not possible to develop drugs without the necessary knowledge about the active substance. The data obtained in Russia makes it possible not only to complete the work that has been started, but also opens the way to the creation of a whole class of antibiotics based on new principles.

Mechanism of action of bottromycin

Skoltech specialists, together with employees of the Kurchatov Institute, discovered the mechanism of action of the antibiotic bottromycin A2. This substance was first synthesized back in 1957 in Germany and has shown the ability to kill those pathogens against which other drugs were powerless. However, in its original form, the molecule was unstable in the blood, so it was not possible to make a full-fledged medicine out of it. To solve this problem, the compound could be modified, but scientists did not fully understand exactly how it affects bacteria, so they could not complete the work. The data obtained opens the way to the creation of a drug against resistant strains of microbes, as well as a whole class of new antibiotics with a similar mechanism of action.

— We conducted many experiments and established the exact mechanism of action of bottromycin A2, and it turned out to be different from all previously proposed options. Moreover, this mechanism is completely new and even unique in comparison with the mechanisms of action of all known antibiotics, which partly explains the long time it took to discover it," said Inna Volinkina, a graduate student at Skoltech.

It turned out that bottromycin harms bacteria in an unusual way. Proteins in a cell are formed from amino acids by the ribosome. Other antibiotics interact with it, thereby disrupting protein synthesis, but bottromycin binds not to the ribosome itself, but to the transporter of one specific amino acid, glycine. Thus, the delivery of the necessary building material of proteins to the assembly apparatus changes, as a result of which the vital processes of the pathogenic bacterial cell are disrupted.

"Our study has demonstrated that bottromycin A2 has a unique mechanism for inhibiting protein synthesis: it selectively blocks translation only in cases where glycine incorporation is required. This discovery not only expands the fundamental understanding of the interaction of antibiotics with bacterial cells, but also opens up new prospects for the development of antimicrobial drugs with a targeted mechanism of action," said Elena Polesskova, senior researcher at the Department of Molecular and Radiation Biophysics at the Kurchatov Institute — PIAF.

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The uniqueness of the mechanism of action of bottromycin makes it impossible to develop cross-resistance to other antibiotics, which is why the substance is promising for the development of new generation drugs. In addition, it is possible that there are other molecules in nature that work by the same (or similar) mechanisms, which opens up new horizons for researchers.

— The logical next step will be the targeted, rational development of modifications of the bottromycin molecule, which will make it more stable and suitable for drugs. We are already thinking over strategies for synthesizing new compounds based on this substance," said Inna Volinkina.

How to overcome resistance

The rate and likelihood of antibiotic resistance largely depend on how "convenient" the target for mutations is. If the drug affects a vital and evolutionarily conservative element of the bacterial cell, then the development of resistance either becomes extremely difficult or is accompanied by a sharp drop in the viability of the microorganism. That is why today the search for new drugs is increasingly focusing on such poorly "bypassed" targets. Therefore, the work of Russian scientists looks particularly relevant against the background of the global antibiotic resistance crisis, Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University, explained to Izvestia.

— The target of bottromycin A2 is indeed one of the highly conservative ones. Transport RNAs and the amino acid delivery system to the ribosome are one of the most ancient and fundamental levels of cell biology, which has remained virtually unchanged during the evolution of bacteria. Glycine tRNA and related processes are critically important for protein synthesis, and any serious mutations in this system are usually incompatible with normal cell growth and survival," the scientist said.

Bottromycin and its future derivatives are particularly promising not only as stand-alone drugs, but also as components of combination therapy, where several antibiotics simultaneously hit different, fundamentally important and weakly mutable targets, he added.

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The introduction into practice of a drug with a new mechanism of action, especially one that makes it difficult to develop resistance, is a very important scientific event, says the leading market expert of NTI "Helsnet" and the union "Health of the Healthy", doctor Andrey Martyushev–Poklad.

— However, there is a gap between a successful experiment and the clinical use of an antibiotic. And the main obstacles to entering the market are related to side effects. Unfortunately, many effective antibiotics have a toxic effect on the close relatives of the bacteria living in our cells— the mitochondria. This means that they disrupt energy production and other vital functions of mitochondria," said the doctor.

Therefore, the discovery of scientists does not guarantee success in creating new drugs based on bottromycin. The main thing is to understand how toxic they will be to human mitochondria, the expert concluded.

The discovery of the mechanism of action of bottromycin A2 is a great scientific success, as it opens the way to the creation of a new class of antibacterial drugs and will allow doctors to obtain a new weapon against infection in the arsenal, said Mikhail Khvostov, Deputy Director of the NSU Institute of Medicine and Medical Technologies for Biomedical Research and Pharmacy.