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January 26 | The FTP 2014-2020

Chasing the strain

After the boom in the middle of the last century, new antibiotics are evolving to the market not so often, and the number of bacteria adapted to the action of the drugs already available steadily grows. This imbalance would render mankind vulnerable to new bacterial infections. Chemists from the Moscow State University are looking for the answer to this challenge. They create a system to search for the new antibiotics, which should lead to creation of new effective drugs in the future.

Штамм-репортер
A cup with a reporter strain. Black circles are the zone of inhibition (bacteria died). The zone of reporter strain’s induction is around the zone of inhibition (fluorescent protein  CER appears)

Standard scheme for new antibiotics’ search usually starts with checking the antibacterial activity of a candidate substance. If it is confirmed that the substance is able to fight the bacteria, the researchers begin to study its action mechanism. This process is complex and lengthy, but it cannot be registered without understanding how the new antibiotic works.

Scientists of the Moscow State University (Faculty of Chemistry) are developing a new, more versatile and convenient engine of antibacterial agents’ search. It allows understanding how the active substance interacts with a target- on a primary screening stage.

The basis of this system is the reporter strain created by scientists - some natural structure capable to recognize when the ribosome stops working (Ribosome is a molecular machine moving on RNA that synthesizes proteins).

"In nature, the ribosome stops if lacking one particular amino acid. We modified it genetically, so that it never cease moving quickly, except when it is blocked by some antibiotic. Thus, we have created a system based on the reporter strain and responds to all substances that stop this protein synthesis machine. And the process of searching the mechanism of action of the antibiotic is greatly simplified, it actually starts when the screening of active substances starts»- Peter Sergiev, the project leader, Professor of Department of Chemistry of Natural Compounds of MSU Faculty of Chemistry, explains his work.

To visualize the operation of the system, the scientists used reporter genes of fluorescent proteins. They illuminate the halo around the zone in which bacteria cells died from antibiotic, by the green light. Thanks to them, the process of interaction of "executioner" and "victim" is easy to analyze, it does not require the additional reagents other than those that are necessary for the cultivation of bacteria.

Physical location of interaction of antibacterial agents is the bacteria cells on the agar surface. A robot that can perform a series of identical operations at the same time is used to test a lot of potential antibiotics immediately. In total, about 10,000 chemically synthesized compounds will be tested during the study.

They are picked mainly by computer predictions (for their ability to connect with sites of RNA) and delivered to the researchers the CHEMRAR high-tech Center acting in this project as an industrial partner.

The expected outcome of the project, i.e. the emergence of a new, reliable, proven engine for antibiotics’ search will significantly shorten the path of new antibacterial drugs’ developing. Moreover, this approach will be of interest not only in terms of the domestic pharmaceutical industry.

"There are similar sensors in the world, but they use the regulatory systems that are sensitive to a particular class of known antibiotics. We put more interesting and challenging task: to create a system that can find a brand new compound, which may be the first in a new class of antibiotics. Our system has a broad specificity. In this sense, there are no any analogues of this unique development abroad" - Peter Sergiev says.

By the way, despite the distrust of antibiotics heated in the public information space, the scientist is convinced that humanity will not be able to get by with these drugs either today or in the foreseeable future.

"On the contrary, in the long term the need for new antibiotics will increase, - Peter Sergiev said. - Today, they are well enough to cope with bacterial infections. But the number of resistant strains of bacteria is growing every year, and it may be that available drugs will not be able to cope with them. So we just have to take part in this race lead by the quickly adapting bacteria, if, of course, we want to treat people from bacterial infections. And the fact that pharmaceutical companies have slightly decreased the interest to antibiotics, what they often publicly stated, is in terms of their business models. It is directly written in some surveys that person takes an antibiotic for a week or two, then either recovers or not. It’s advantageous for drug manufacturers when their products are taken for decades by patients. Therefore, they are more focused on developing the drugs that are used against chronic diseases, but it is only the money issue. I think that we should be more interested in human health."

The project "Development of high-performance systems to detect the antimicrobial drugs" is supported by the Federal Target Program "Research and development in priority areas of scientific and technological complex of Russia for 2014-2020"

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