Mechanisms of antibiotic resistance
Recently, antibiotic resistance has become the number one problem in the pharmacological industry that develops antimicrobials. The thing is that it is inherent in almost all known varieties of bacteria, so antibiotic therapy is becoming less effective. Such common pathogens as Staphylococci, Escherichia coli and Pseudomonas aeruginosa, the proteins have resistant strains that are more common than their ancestors exposed to antibiotics.
Resistance to various groups of antibiotics, and even to individual drugs, develops in different ways. Old good penicillins and tetracyclines, as well as newer developments in the form of cephalosporins and aminoglycosides, are characterized by a slow development of antibiotic resistance, in parallel with these, their therapeutic effect also decreases. What can not be said about such drugs, the active substance of which is streptomycin, erythromycin, rifampicin and lincomycin. Resistance to these drugs develops at a rapid pace, in connection with which the appointment has to be changed even during the course of treatment, without waiting for its termination. The same goes for preparations of oleandomycin and fusidine.
All this gives grounds to assume that the mechanisms of development of antibiotic resistance to various drugs are significantly different. Let's try to understand which properties of bacteria (natural or acquired) do not allow antibiotics to produce their irradiation, as originally conceived.
To begin with, we determine that the resistance of a bacterium can be natural (protective functions given to it initially) and acquired, which we discussed above. So far, we have mainly talked about the true antibiotic resistance associated with the characteristics of the microorganism, and not with the incorrect choice or prescription of the drug (in this case it is a false antibiotic resistance).
Every living being, including the simplest, has its own unique structure and some properties that allow it to survive. All this is laid down genetically and transmitted from generation to generation. The natural resistance to specific active substances of antibiotics is also laid down genetically. And in different types of bacteria, resistance is directed to a certain type of drugs, which is why development of various groups of antibiotics affecting a particular type of bacteria is associated.
Factors that cause natural resistance may be different. For example, the structure of the protein membrane of a microorganism can be such that an antibiotic can not cope with it. But antibiotics can only be affected by a protein molecule, destroying it and causing the death of a microorganism. The development of effective antibiotics implies taking into account the structure of the proteins of bacteria against which the action of the drug is directed.
For example, the antibiotic resistance of staphylococci to aminoglycosides is due to the fact that the latter can not penetrate the microbial membrane.
The whole surface of the microbe is covered with receptors, with certain types of which are associated with AMP. A small number of suitable receptors or their complete absence lead to the fact that there is no binding, and hence the antibacterial effect is absent.
Among other receptors there are also those that for the antibiotic serve as a kind of beacon signaling the location of the bacteria. The absence of such receptors allows the microorganism to hide from danger in the form of AMP, which is a kind of disguise.
Some microorganisms have a natural ability to actively withdraw AMP from the cell. This ability is called effluksom and it characterizes the resistance of Pseudomonas aeruginosa against carbapenems.
Biochemical mechanism of antibiotic resistance
In addition to the natural mechanisms of development of antibiotic resistance listed above, there is one more that is related not with the structure of the bacterial cell, but with its functional.
The fact is that in the body of bacteria, enzymes can be produced that can have a negative effect on molecules of the active substance AMP and reduce its effectiveness. Bacteria when interacting with such antibiotic also suffer, their effect is markedly weakened, which creates the appearance of curing infection. Nevertheless, the patient remains a carrier of bacterial infection for some time after the so-called "recovery".
In this case, we are dealing with a modification of the antibiotic, as a result of which it becomes inactive with respect to this type of bacteria. Enzymes produced by different types of bacteria may differ. Staphylococcus is characterized by the synthesis of beta-lactamase, which provokes the rupture of the lactem ring of antibiotics of the penicillin series. The development of acetyltransferase can explain the resistance to chloramphenicol gram-negative bacteria, etc.
Acquired antibiotic resistance
Bacteria, like other organisms, are not alien to evolution. In response to "military" actions against them, microorganisms can change their structure or start synthesizing so much of an enzyme substance that can not only reduce the effectiveness of the drug, but also destroy it completely. For example, the active production of alanine transferase makes "Cycloserine" ineffective against bacteria that produce it in large quantities.
Antibiotic resistance can also develop due to a modification in the cell structure of the protein, which is also its receptor, to which AMP should bind. Those. This kind of protein may be absent in the bacterial chromosome or change its properties, as a result of which the connection between the bacterium and the antibiotic becomes impossible. For example, the loss or modification of a penicillin-binding protein causes insensitivity to penicillins and cephalosporins.
As a result of the development and activation of protective functions in bacteria previously susceptible to the destructive effect of a particular type of antibiotics, the permeability of the cell membrane changes. This can be done by reducing the channels through which the active substances of AMP can penetrate into the cell. It is these properties due to the insensitivity of streptococci to beta-lactam antibiotics.
Antibiotics can influence the cellular metabolism of bacteria. In response, some microorganisms learned to do without chemical reactions, which are affected by the antibiotic, which is also a separate mechanism for the development of antibiotic resistance, which requires constant monitoring.
Sometimes bacteria go to a certain trick. By joining to a dense substance they are united in communities called biofilms. Within the community, they are less susceptible to antibiotics and can safely tolerate dosages killing for a single bacterium that lives outside the "collective".
Another option is to combine microorganisms into groups on the surface of a semiliquid medium. Even after cell division, a part of the bacterial "family" remains inside the "grouping", which can not be influenced by antibiotics.
Genes of antibiotic resistance
There are concepts of genetic and non-genetic drug resistance. With the latter, we are dealing with when we consider bacteria with inactive metabolism, not prone to multiplication under normal conditions. Such bacteria can develop antibiotic resistance to certain types of drugs, nevertheless, this ability is not transmitted to their offspring, since it is not genetically incorporated.
This is characteristic of pathogenic microorganisms that cause tuberculosis. A person can get infected and not suspect about the disease for many years, until his immunity for some reason will not fail. This is the trigger for multiplication of mycobacteria and the progression of the disease. But all the same drugs are used to treat tuberculosis, the bacterial progeny still remains sensitive to them.
The same is true with the loss of protein in the cell wall of microorganisms. Remember, again about bacteria that are sensitive to penicillin. Penicillins inhibit the synthesis of the protein that serves to build the cell membrane. Under the influence of AMP penicillin series microorganisms can lose the cell wall, the building material of which is the penicillin-binding protein. Such bacteria become resistant to penicillins and cephalosporins, which now have nothing to communicate with. This phenomenon is temporary, not related to the mutation of genes and the transfer of the mutated gene by inheritance. With the appearance of the cell wall, which is characteristic of previous populations, the antibiotic resistance in such bacteria disappears.
The genetic antibiotic resistance is said to occur when changes in the cells and metabolism within them occur at the gene level. Mutations of genes can cause changes in the structure of the cell membrane, provoke the production of enzymes that protect bacteria from antibiotics, and also change the number and properties of the receptors of the bacterial cell.
There are 2 ways of development of events: chromosomal and extrachromosomal. If a gene mutation occurs on that part of the chromosome that is responsible for sensitivity to antibiotics, they speak of chromosomal antibiotic resistance. By itself, such a mutation occurs extremely rarely, usually it causes the effects of drugs, but again, not always. It is very difficult to control this process.
Chromosomal mutations can be transmitted from generation to generation, gradually forming certain strains (varieties) of bacteria resistant to one or another antibiotic.
Culprits of extrachromosomal resistance to antibiotics are genetic elements that exist outside the chromosomes and are called plasmids. It is these elements that contain the genes responsible for the production of enzymes and the permeability of the bacterial wall.
Antibiotic resistance is most often the result of horizontal gene transfer, when some bacteria transmit some genes to others that are not their descendants. But sometimes unconnected point mutations can be observed in the genome of the pathogen (size 1 in 108 for one process of copying the DNA of the mother cell, which is observed when replicating chromosomes).
So in the fall of 2015, scientists from China described the gene MCR-1, found in pig meat and swine intestines. A feature of this gene is the possibility of its transmission to other organisms. After a while, the same gene was found not only in China, but also in other countries (USA, England, Malaysia, European countries).
The antibiotic resistance genes are able to stimulate the production of enzymes that were not previously produced in the body of bacteria. For example, the enzyme NDM-1 (metal beta-lactamase 1), found in bacteria Klebsiella pneumoniae in 2008. At first it was found in bacteria from India. But in subsequent years, an enzyme providing antibiotic resistance against most AMP was detected in microorganisms in other countries (Great Britain, Pakistan, USA, Japan, Canada).
Pathogenic microorganisms can be resistant to certain drugs or groups of antibiotics, as well as to different groups of drugs. There is such a thing as cross-antibiotic resistance, when microorganisms become insensitive to drugs with a similar chemical structure or mechanism of action on bacteria.
Antibiotic resistance of staphylococci
Staphylococcal infection is considered one of the most common among community-acquired infections. However, even in a hospital on the surfaces of various objects, it is possible to detect about 45 different strains of staphylococcus. This suggests that the fight against this infection is almost the first priority of health workers.
The difficulty in accomplishing this task is that most strains of the most pathogenic staphylococcus Staphylococcus epidermidis and Staphylococcus aureus are resistant to many types of antibiotics. And the number of such strains is growing every year.
The ability of staphylococci to multiple genetic mutations, depending on the habitat conditions, makes them virtually invulnerable. Mutations are transmitted to descendants and in a short time there are whole generations of infectious agents resistant to antimicrobial preparations from the genus Staphylococci.
The biggest problem is methicillin-resistant strains that are resistant not only to beta-lactams (β-lactam antibiotics: certain subgroups of penicillins, cephalosporins, carbapenems and monobactams), but also to other types of AMP: tetracyclines, macrolides, lincosamides, aminoglycosides, fluoroquinolones, chloramphenicol.
For a long time, the infection could be destroyed only with the help of glycopeptides. At present, the problem of antibiotic resistance of such strains of staphylococcus is solved by means of a new type of AMP - oxazolidinones, whose bright representative is linezolid.