Researchers are studying early stages of ribosome formation to identify new targets for antibiotics

Ribosome formation is viewed as a promising potential target for new antibacterial agents. Researchers from Charité – Universitätsmedizin Berlin have discovered new insights into this multifaceted process.

The formation of ribosomal components involves a number of auxiliary proteins that, like instruments in an orchestra, interact in a coordinated manner. One of these helper proteins – ObgE proteins – acts as a conductor, directing the whole process. The research, which made the first reconstruction based on an image of this process, was published in Cell molecular.

Ribosomes are an essential part of every living cell. Often referred to as ‘molecular protein factories’, they translate genetic information into chains of linked amino acids called proteins.

The process of protein biosynthesis is the same in all cells, even in bacteria (including the widely known intestinal bacterium Escherichia coli). If this process cannot occur, the cell dies; a single-celled organism (such as E. coli and other bacteria) cannot survive. Researchers hope to take advantage of this situation for the development of novel antibiotic agents.

The need for these new drugs is not only due to an increase in antibiotic resistance and the emergence and spread of new multidrug-resistant pathogens, but also because there has been a long time since exposure. a new class of antibiotic products. A new type of antibiotic can be designed to prevent ribosome formation in a way that prevents their assembly.

It is a coincidence that we are currently in the midst of a viral pandemic. The next pandemic may be of bacterial origin as both bacterial antibiotic protection and multidrug resistance spread rapidly, over species barriers.. “

Dr Christian Spahn, Last Study Author and Professor, Director of Medical Physics and Biophysics, Charité – Universitätsmedizin Berlin

He said: “The long-term goal of our basic research is to contribute to the development of new antibiotics.” Working with colleagues from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin and the University of Konstanz, Charité researchers investigated the early stages of ribosome formation to identify points in the process that could be targets. for new antibacterial and antimicrobial drugs.

Ribosomes consist of two subunits: one larger subunit and one smaller one. As part of their latest efforts, the team, led by Dr. Rainer Nikolay of the Charité Institute for Medical Physics and Biophysics, focus on the study of the nature and development of the larger ribosomal subunit in the bacterium E.coli.

Attempting to identify a potential target for new antibiotics, the researchers wanted to separate and see the prior levels of this larger subunit. To do so, they wanted to use the subunit in its non-dispersive form, ie as close to the natural position as possible.

For the first time, the researchers succeeded in not only separating one such precursor from bacterial cells (in this case, E. coli), but also seeing it using microscopy images. cryo-electron at near-atomic resolution. “We now have a better understanding of how the larger bacterial ribosomal substrate develops at the molecular level, although our understanding is still far from complete,” says the first author, the Dr. Nikolay.

The research team chose a protocol that was so minimally invasive to the extent that the bacterial cell would need to be treated. One of the main agents in the ribosome formation process, the ObgE protein, has been identified using what is known as the ‘Strep tag’. This step involves a ‘gene insert’ procedure – inserting genetic information into the bacterial genome. Such a treated bacterium can only produce ObgE marked. After microfiltration of the cell, this ObgE can then be viewed using an electronic microscope. The Strep tag allowed the researchers to explore the entire building for the first time. This is because the ObgE helper protein effectively carries the precursor of the largest ribosomal subunit on its back. The results came as a surprise, as Dr. Nikolay explains: “We found that this precursor is encased in a number of helper proteins, which either interact or interact. communicate directly with each other.The ObgE protein plays a key role in this process, effectively directing and coordinating it. “This could be a target for new drugs, which may stop inhibit bacterial growth by inhibiting the accumulation of active ribosomes.

The team wants to use similar strategies to gain further insight into the development of bacterial ribosomal substrate and to advance their understanding of the relevant biological processes at the molecular level.

Previous research, conducted at Charité and the Max Planck Institute for Molecular Genetics, had uncovered valuable information about the basic structure of ribosomes and the various stages of the maturation process required by these cellular protein factories. While all of the previous observations were based on in vitro studies, the researchers knew that the formation of the large chromosomal subunit can only be seen in a living cell.

So the latest step in the efforts has been a crucial one: to identify new cell drug targets, it is necessary to understand how the process of ribosome formation seen in bacteria differs from the process in human cells.

“We have been able to make significant progress in this regard,” said Dr Nikolay. “We have been able to report that prokaryotes – such as bacteria – and eukaryotes – are organisms with genetically informed information. inside a cell nucleus. ”These decisions are important if we are to focus on bacteria-specific traits while also protecting human cells from unwanted effects.