For the first time in 50 years, a new class of antibiotics acting on gram-negative bacteria
Well, guys, will we enjoy the new achievement, which, it is said, was the light at the end of the tunnel?
The widespread, unjustified use of these drugs both in clinical practice and in agriculture has led to the emergence of microorganisms resistant to all types of existing antibiotics.
People who are not related to medicine do not know that in the hospitals of such countries as, for example, Belarus and the Russian Federation, the catastrophe is happening right now. Due to the lack of proper epidemiological surveillance, inept use of medicines, lack of funding, lack of competent microbiological support (there are no normal microbiologists and equipment for determining the minimum inhibitory concentrations (MIC) *), and, importantly, because of the general criminal concealment of the existing problem , people here and there are dying from nosocomial infections ** (VBI) caused by such microorganisms.
While VBI did not break out of the hospital threshold, and we - did not hit it, you can do poker face and do not notice this approaching fucking, which crept up completely unnoticed.
Nevertheless, those most insatiable pharmaceutical companies, driven exclusively by greedy profit maximizers, committed 3-3337. kimming-out [/s] what is now being talked about from every iron - have developed a fundamentally new class of antibacterial agents capable of holding us in jumping into a deep chasm of total multiple antibiotic resistance.
This I want to tell you a little.
Among important antibiotic-resistant microorganisms that are easily remembered by the acronym ESKAPE, the most difficult for clinicians are gram-negative microorganisms (hereinafter G-).
A feature of these bacteria is the presence of two membranes, external and internal, which make it difficult for antibiotics to enter their cells. All those antibiotics that entered the market in the last 50 years were rehashes, that is, modifications of those long-open classes that, as already mentioned, ceased to act on the microbial cell. And the need for new solutions is not just ripe, but even overripe.
One of the most common strategies for the development of medicines is the search for a suitable natural compound with at least minimal activity and subsequent modification to enhance the desired properties. In this case, they did so.
Attention was drawn to the so-called arylomycins, a class of macrocyclic lipopeptides that inhibit Type 1 bacterial signal peptidase (SP I). It should be noted that these arylomycins have been interested for 20 years already, but this has not resulted in any significant success. Probably because the researchers were mainly engaged in CI I Gram-positive microorganisms (hereinafter - G +).
Before proceeding, we need to make a few explanations for the unsophisticated public, which, as I understand it, is 99.9% of my audience.
What is a macrocyclic lipopeptide? [/b]
Macrocycles in chemistry are called compounds in which there are cycles formed by at least 12 atoms. A peptide is a compound that consists of a small number of amino acids. Lipo-root, as you might guess, means the presence in the molecule of a certain lipid part, the remainder of the fatty acid in this case.
What is a signal peptidase? [/b]
Peptidase is an enzyme of the hydrolase class, which breaks down proteins. The result of the operation of hydrolases is completely analogous to non-enzymatic hydrolysis, that is, to the process proceeding under the action of water.
So, SP I splits the proteins. But why is it called signaling?
In any cell, not necessarily bacterial, there are many proteins that, in order to perform their function, must not be located directly in the cytoplasm, but in the cell membrane itself or even beyond its limits. In order to distinguish them from other proteins that are not required beyond the cytoplasm, the cell in the process of translation marks them with a special signal sequence of amino acids that serves as a target for transport mechanisms that help move the protein to or out of the membrane. Accordingly, the SPs cut off these signal sequences during such a movement, turning "non-protein" into a mature functional polypeptide.
Actually, hence the interest in the joint venture as a target of medicines is clear. In the event that the signal portion of the amino acid sequence is not cut off during the cut off, the normal protein molecule will not receive the cell with all the ensuing consequences in accordance with the definition of life according to Engels.
In G + SP I is located in the cytoplasmic membrane in such a way that its part protrudes outward and is completely accessible to arylomycins. However, in G- it is in the periplasmic space, and for a long time the researchers believed that arylomycins can not penetrate through the outer membrane, so there is nothing to try. Do not be like researchers!
It turned out that arylomycins can still penetrate through the outer membrane, just the I G- SP has a mutation in one of its domains (part of a protein molecule with a certain function or a certain position relative to other domains), which makes it less vulnerable to this class of inhibitors.
Therefore, an idea arose by modifying a natural molecule to achieve 2 things:
a) improve the penetration of arylomycin through the outer membrane;
b) strengthen the binding of the molecule of the modified antibiotic with SP I to enhance the bactericidal effect.
Let's see how it was possible to reach the team from the pharmaceutical company Genentech, which took as prototype arylomycin C16 (A-C16).
First, after studying the X-ray diffraction patterns of the complex of SP I with A-C1? it became clear that the macrocyclic part of A-C16 binds to the conserved part of the protein molecule of SP I, which led the researchers to the conclusion that it should not be "touched".
Secondly, it was known that natural arylomycins differing in fatty acid tails have different antimicrobial activity, and in A-C16 it is not optimal for interaction with SP I. Thus, it was decided to modify this fragment of A-C16. Part of the amino acid units was replaced with diaminobutyric acid, and the palmitic acid residue was replaced by a complex aromatic substituent. As a result of these manipulations, the activity with respect to G-was slightly improved.
Thirdly, it was also known that the C-terminus of arylomycins, that is, the last amino acid in the chain, also affects the bactericidal activity. Genentech chemists were replaced in the second-molecule modified carboxyl group by 2-aminoacetonitrile. This led to the fact that, according to the researchers, the amino acid lysine, located in the active center of SP I, now binds to the inhibitor with a strong covalent bond, as a result, the active center of the enzyme remains permanently blocked. Thus, the contact of two molecules, a protein and a low molecular weight arylomycin, is prolonged, and the bactericidal activity of the latter is increased.
And, finally, in the fourth place, it was decided to juggle phenolic residues with hydroxyl groups, since, again, according to the published data, their modification changed the activity of related compounds. As a result, dimethyleneamine groups were hung on them, which further reduced the minimum inhibitory concentration not only with respect to G-, but also in relation to G + of the ESKAPE group.
As it turned out, the obtained compound under the code number G0775 turned out to be very active in relation to the toothy animals living in the clinic (and not only laboratory strains), which is resistant to many classes of known antibiotics. The following table shows comparison of the MIC of the developed compound with MIC of other antibiotics with respect to the antibiotic-resistant Klebsiella strain:
In addition to microbiological data, the article presents studies of the developed antibiotic on infected mice, which confirm the safety and efficacy of the new drug and, hopefully, will serve as a starting point for its introduction into clinical practice.
Now a little bit of my own thinking in prison.
Undoubtedly, as I wrote metaphorically in the introduction, a new class of antibiotics, if it will be introduced into clinical practice (and it will be clearly under the abbreviated program due to the cramming in the US with the VBI), will not become a panacea. Nobody canceled mutational variability. In the article itself, by the way, it was demonstrated the formation of G0775-resistant strains with prolonged contact of bacteria with high doses of antibiotics. And I'm afraid if none of the devastation that is in the heads of the power of those who hold and those who are on the upper floors of the managerial pyramid in health care will change, G0775 will remain in the memory of clinicians as a short bright band in a series of carefully hidden deaths from VBI.
From the chemical point of view, in my opinion, the article does not represent anything supernatural. And yet, despite the fact that the approach used is in the drug development classics, I dare say that, for example, in many countries this kind of development is simply impossible for many reasons.
First, I think that Genentech's own budget exceeds the budget of several countries several times. Secondly, as it follows from my summary, a multidisciplinary approach should be used to develop new drugs, which is impossible in a completely bureaucratic environment. Specifically in this case, 9 different divisions of the company were engaged in research: microbiologists, chemists, pharmacists, structural biologists, bioinformatics and others.
Note: in fact, Genentech used data already known from the literature for its work on directed modification of arylomycins. Alas, in the post-Soviet countries there are not so many scientific teams that can monitor what is happening in their field at the international level and successfully integrate world experience into their achievements, including for a banal reason: they can not read specialized literature on English.
Yes, I would like to hope that such components of Genentech's success as persistence in achieving the goal and belief in their own strengths, outside of big pharma still exist, but it is absolutely clear that in today's dynamic world, a system that tries to live by the past by all means is doomed to failure.
* minimum inhibitory concentration (MIC) - the minimum concentration of antibiotic that inhibits the multiplication of the microorganism.
** Nosocomial infections (VBI) are clinically significant diseases of microbial origin that affect a patient as a result of his hospitalization or visit to a medical institution for treatment, or within 30 days after discharge from hospital, and hospital staff due to his activities, regardless of whether or not the symptoms of this disease are manifested during the finding of these persons in the hospital.
For acquaintance with the situation on antibiotic resistance in the Russian Federation, you can see roller .
For a summary of the article under discussion, see here .
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