Antibiotics of the future

Ada Yonat's lecture at NAUKA 0+ Festival

Oksana Shlyakhtina, "Scientific Russia"

Ada Yonat, Nobel Prize winner in Chemistry, Head of the Biomolecular Structure Center at the Weizmann Institute in Israel, delivered an online lecture on "New Generation Antibiotics" as part of the NAUKA 0+ All–Russian Science Festival. She told about how modern antibiotics work, how they affect the environment and what medicines are waiting for us in the future.

Ribosomes

Deoxyribonucleic acid (DNA) encodes amino acids of various proteins that are required by the human body. This process takes place in several stages. First, a copy similar to an mRNA molecule is formed from DNA, after RNA – a single helix. Then the process of translation of RNA into proteins takes place with the help of a ribosome. It happens all over our body.

Ribosomes perform two main functions:

• decoding of peptide bonds
• production of proteins.

Ribosomes can form up to 45 peptide bonds in one second.

Ribosomes consist of two subunits. Yonat compared the work of ribosomes with the work of a factory. "They look like a factory with two floors. The first floor reads the genetic code, the lower floor of the plant produces proteins. Trucks bring various protein fragments, there are three bases in each produced code. Amino acid coding takes place, that is, amino acids arrive and join the growing protein chain – this is what happens in the ribosome on the first floor of our plant. When proteins join, the chain increases by one amino acid, our trucks leave empty. Energy is involved in this process, it is an energy–dependent process, and this is how DNA comes from us," she explained. Scientifically speaking, ribosomes consist of small and large subunits. The small one is responsible for translation and decoding, the large one is responsible for creating peptide bonds. Trucks are a tRNA molecule. There, the amino acid is decoded and added to the growing protein chain.

Ribosomes are present in every cell of the body in huge quantities, including bacterial ones. Ribosomes are important in the work of antibiotics. About half of the antibiotics stop the biosynthesis process by paralyzing the ribosome.

For example, erythromycin is one of the first ribosomal antibiotics that we widely use. It attaches to the tunnels and blocks the exit of proteins from the tunnels. Tetracycline is a very small antibiotic that prevents the process of tRNA binding to the A-site. Clindamycin blocks the formation of peptide bonds. All antibiotics work by blocking functional sites in ribosomes. Functional sites are something that is found in all living organisms, including bacteria. These sites have very low variability, and this is what leads to antibiotic resistance – the resistance of bacteria to antibiotics due to various mutations. In addition, bacteria create various signaling molecular pathways that lead to antibiotic resistance.

In this regard, scientists faced the task of creating an antibiotic to which bacteria have no resistance. The problem of antibiotic resistance has acquired such proportions that scientists say that we are approaching an era when antibiotics will become ineffective. Pharmaceutical companies do not want to produce antibiotics because of the discrepancy between their social significance and the height of the costs of their creation.

A new generation antibiotic

Ada Yonat noted that it is impossible to completely get rid of antibiotic resistance of bacteria. "We will not be able to overcome the process of antibiotic resistance, because bacteria are smarter than us in terms of survival. We decided to do everything to control the process of antibiotic resistance, and to reduce the resistance of bacteria," she said.

The researcher said that in order to create new antibiotics, it is necessary to work not with active sites, but with motifs that are located on the periphery of ribosomes. Because of their location, not a single bacterium has resistance. The concept of scientists has become this: to create antibiotics of a narrow spectrum of actions in order to reduce the risk of creating antibiotic resistance. 

After conducting a number of studies, scientists have found out that all bacterial ribosomes are very similar to each other. They concluded that a small patch of pathogenic bacteria could become a potential binding site. The researchers identified 25 such sites and tried to block them alternately, and blocking 16 of these sites led to inhibition of protein biosynthesis. Such sites are not involved in the main ribosomal activity, so they are unlikely to lead to modification of bacteria. This means that at the moment ribosomal sites can be used to create fully degradable antibiotics that will not cause damage to the environment and humans, killing microbiomes – beneficial bacteria. New antibiotics will be able to distinguish different types of bacteria.

Environmental consequences of the use of antibiotics

The use of antibiotics affects the environment. Most modern antibiotics are small organic molecules that are produced by bacteria. They cannot decay, and cannot be digested by eukaryotes. Antibiotics are released from the body and enter the soil. Since these molecules are very small, they infect the environment and they are very toxic. Then they get back into our body through the consumption of meat and milk. This is what increases a person's resistance to antibiotics.

Through the creation of new antibiotics, scientists want to eliminate this factor and abandon small organic compounds by inhibiting protein biosynthesis with the help of new potential binding sites. It is also proposed to use biodegradable molecules, for example, nucleic acids or peptides, and make antibiotics non-toxic.

Almost half of antibiotics are aimed at inhibiting the work of ribosomes. Cells have developed a special method of self-preservation when exposed to a stress factor, which leads to the production of ribosome dimers. How does it work? A dimer of two ribosomes: one ribosome blocks the second ribosome due to the fact that it blocks the binding points of factors. This is how cells guard their own ribosomes. Each type of cell has its own way of producing such dimers. Scientists are also planning to use them to develop new antibiotics. "We need to develop such antibiotics that will be pathogen-specific, that is, aimed specifically at blocking pathogens. We must create separate antibiotics for each type of pathogen in order to reduce the degree of destruction of beneficial bacteria that make up our microbiome," Ada Yonat summed up her lecture.

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