University scientists to develope a new way to fight tuberculosis

09:04, August 22, 2019

Some compounds are effective against the drug-resistant form of the disease

Tuberculosis remains one of the most dangerous and obstinate diseases. A team of chemists from Ural Federal University together with their colleagues from Postovsky Institute of Organic Synthesis and Vavilov Institute of General Genetics synthesized a number of imidazotetrazine-based chemical compounds and tested their influence on the harmful bacteria. The article was published in the European Journal of Medicinal Chemistry.

Tuberculosis is caused by the bacteria of the Mycobacteriaceae family. They form mycelium-like structures and often live in human lungs. The purpose of annual fluorography is to diagnose tuberculosis on an early stage. Mycobacteria quickly develop drug resistance causing the doctors to use more expensive and toxic substances in the course of treatment that poison both the bacteria and healthy tissues. If the scientists were able to identify a specific target, they would be able to affect only the Mycobacteria. Identifying such a target would revolutionize the whole anti-tuberculosis drug industry, especially if the bacteria were unable to develop resistance to such drugs.

A Russian research group chose imidazotetrazine derivatives as a basis for developing new drugs. These molecules are very similar to purines — DNA components that are widely spread in nature. However, the synthesized substances have more nitrogen atoms in their structure. This structural feature gives the molecules specific properties, thus making them active against various biological targets. One of such targets is the enzyme called serine/threonine protein kinase (STPK) that plays an important role in the survival of the Mycobacteria. In harmful bacteria this enzyme modifies other proteins by means of adding a phosphate to them and regulating their activity. Scientists suggest that the new drugs might bind with STPK in tuberculosis bacteria and block its activity.

To prove the efficiency of the new substances, the scientists grew the cultures of mycobacteria and monitored their reaction to the drugs. The growth of their colonies stopped around a paper disc soaked in imidazotetrazines. The group confirmed that the bacteria were able to develop resistance to the substances under consideration, but it was different from resistance to standard antibiotics due to difference in targets: antibiotic-resistant strains were sensitive to imidazotetrazines, and vice versa. The scientists selected the most effective molecule out of the 10 synthesized ones and plan to further improve its solubility.

“The collaboration of chemists and biologists helped us not only to create new compounds and to reveal their activity against the mycobacterium tuberculosis, but also to suggest their mechanism of action and to study the ability of mycobacteria to develop resistance to new drugs. These are extremely important data as mycobacteria of tuberculosis mutates very fast, thus forming drug resistant strains. As a result, the efficiency of existing drugs reduces dramatically causing considerable issues in modern anti-tuberculosis therapy. The new mode of action and relatively low frequency of drug resistance mutants’ emergence allows us to consider imidazotetrazine derivatives as promising new anti-tuberculosis agents,” said Svetlana Tolshchina, a Candidate of Chemistry, a junior researcher at the Department of Organic and Biomolecular Chemistry of the Ural Federal University, and a researcher at the Laboratory of Heterocyclic Compounds of the Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences.