The definition in corals bactericidal agent can be an effective tool in the fight against tuberculosis. Scientists have found that artificially synthesized analogue of this substance works best natural and, moreover, it does not harm humans and overcomes the resistance of Koch bacillus causes tuberculosis to antibiotics. The results of the research group, supported by a grant from the Russian Science Foundation, have been published in the journal Chemistry-A European Journal, several papers prepared for publication. The head of the research project, Alexander Rubtsov told the Department of Science of the work done and on what scientists are still problems to be solved.
What is tuberculosis?
The infectious nature of TB has been proven by the German scientist Robert Koch in 1882. It was he who opened the disease-causing mycobacteria Mycobacterium tuberculosis (or Koch’s bacillus). Latin prefix myco- can be translated as “mushroom” and “wax”: in this case it means “wax-like” components contained in the cell wall and protects the bacteria. With the active form of tuberculosis tubercle bacillus multiplies rapidly in various human organs (most often – in the lungs), poisoning the body products of their vital activity
Along with the blood and lymph, it spreads around. body.
The methods of tuberculosis control is divided into two areas: vaccination and development of new medicines. The idea, supported by RNF, is to study the mechanism of action of a new class of substances on the mycobacteria that in the future may allow the creation of a new class of antibiotics. The project aims to search for new mechanisms of influence on the mycobacteria with a view to the subsequent creation of highly effective and non-toxic anti-tuberculosis agents.
The drugs are toxic, resistant bacteria
«A lot of people die from the toxicity of drugs. For more effective TB control need less toxic drugs. The second problem is multidrug-resistant bacteria Mycobacterium tuberculosis », – says the project manager Alexander Rubtsov. The project involves microbiologists, medical microbiologists, chemists synthetics, as well as cooperates with Professor Andrei Malkov from Loughborough University, United Kingdom (Loughborough University).
«The equipment purchased at selected under the program of development of the Perm National Research University funds, allows the study to date, but without the support of RNF conduct these studies would be practically impossible, – says Alexander Rubtsov. – Only a large part of the grant for 2015 was spent for the purchase of chemicals, bacterial media and various consumables for devices. Complex equipment purchased by HSE program and the grant RNF allows you to view the ongoing research on a completely different level of work in frontier areas of science and publish results in leading journals. »
At the bacteria M. tuberculosis develops multidrug antimicrobial resistance. Mycobacterium adapt to antibiotic action, quickly mutating and reducing its effect to naught. As a result, the patient makes his drug resistance to the drug, which was treated. The same principle lies at the heart of action of TB BCG vaccine (Russian transcription of the name of culture Bacillum Calmette Guerin, BCG).
Diagnosis of tuberculosis known reaction Mantoux, “a button”, which are all afraid to wet the school.
Now to the fore new methods of diagnosis of tuberculosis:. Molecular rapid tests HpertMTB / RIF
Corals tuberculosis
Previously, scientists have found that sea corals found belonging to the class of terpenes substance having a strong bactericidal effect. Terpenes – a class of hydrocarbons – biosynthetic products of the general formula (C5H8) n with carbon skeleton formally derived from the isoprene are (C5H8). The number of carbon atoms in the formula any terpene five fold: to get more complex terpenes, need to “lay down” several molecules of isoprene. For example, most of monoterpenes (C10H16) are the main components of essential oils. The names of all terpenes are derived from the Latin name of a natural object from which they identified: betulin (Latin Bétula – birch.), Menthol (Latin Méntha – mint.)
main. components of essential oils are terpenes, terpenes but not all – essential oils. For example, rubber is polyterpenes, but no essential oil.
Among the large number of connections with one of the most promising in the fight against M. tuberculosis is a diterpene called erogorgiane (C20H32), derived from marine coral class Pseudopterogorgia elisabethae. The problem is his isolation from a natural source was the fact that to obtain a sufficient number of erogorgiane required to process a huge amount of biomass a rare species of corals. Therefore, for further practical use of this compound had to be synthesized.
In order to obtain the desired diterpene used asymmetric synthesis method. Asymmetric center (or the stereo-center) in the organic molecule is not nothing but a carbon atom. Asymmetric it because in the arrangement relating to the carbon atoms may be some differences. For example, methane CH4 they have: four hydrogen atoms are bound to the same carbon atom of the chemical bonds, i.e. the methane molecule is symmetrical. In the case of carbon surrounded by various atoms and groups, then the random change of their places in the molecule can greatly affect its chemical properties.
Mirror molecule
Some organic molecules differ only in that they are mirror images of each other. Such substances are called stereoisomers, they possess chirality – they can not be turned so that left and right parts are fully aligned with each other, just as our right hand never coincide with the left, as if we have them or rotated. By the way, the word “chirality” is derived from the Greek χειρ – «hand.” This phenomenon leads to the fact that one molecule to the biological target is suitable and the other – no, like a three-dimensional mosaic
Therefore, for medicines is important to have asymmetric centers was strictly defined configuration. .
As a result of the synthesis of a mixture of two “mirror” stereoisomers. Nature smarter substances produced naturally cleaner, they consist of a single stereoisomer. synthetic chemists task is to shift the equilibrium of the reaction toward a particular stereoisomer, as in nature. For this purpose, organocatalysts – organic substances, which are formed due to the addition of one isomer
To see which of the stereoisomers is active in M. tuberculosis, researchers synthesized various stereoisomers and then tested their activity.. It was found that it is best synthetic analogue of the natural erogorgiane.
Currently used drugs and compounds undergoing clinical trials, have nothing to do with the structure of diterpenes. Nevertheless obtained in 2015, the results showed that the diterpene erogorgiane TB shows promising activity against strains of M. tuberculosis MDR. Terpenes are generally not toxic to humans in an amount of more than 3 g per kilogram of body weight. At least, the acute toxicity was detected in the 24 hours after administration of the drug does not appear.
How far is it to the medicine?
«What is the mechanism of action of terpenes to bacteria?” -. The issue is mainly to the creation of a new drug, and is still open
«On the creation of the drug, the active ingredient will diterpene erogorgiane, it makes sense to say that we fully understood the mechanism of its action on bacteria. This is the purpose of our project. The invention of new drugs – the process expensive and extended, as a rule, it has been delayed for 10-15 years “, – says Alexander Rubtsov
On the creation of a drug is required of $ 500 million. up to $ 3 billion.
By simulating and studying the properties of new materials and mechanisms of their interaction with the “target” (in this case it is caused by bacteria Mycobacterium tuberculosis), scientists find an active substance (hit-compound) which can be used for the production of a new medicament. Next, the resulting compound is finalized before the prototype compounds (lead compound) by improving its properties (permeation properties, solubility in water, chemical stability in the human body and others.). Meanwhile Pharmtechnology determine the form in which the medicine should be to maximize its effectiveness. When the optimal properties of the compound selected, it is time to test the drug. First, its activity, toxicity, mutagenicity tested on animals – this stage is called pre-clinical trials. Then the medicine is patented, and it is followed by three phases of clinical trials of the drug in humans.
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