Until before the coronavirus, one of the greatest public health challenges was the increasing presence of antibiotic-resistant bacteria which were increasingly appearing in both hospital and community settings. The acquisition by these bacteria of resistance to common antibiotics is occurring in both the hospital and community settings. when the use of these antibiotics becomes widespread and leads to a pressure of large-scale selection which allows only the most resistant bacteria to remain infected. Clinical practice foresees this first scenario and relies on second-line antibiotics which are usually more effective and, conversely, cause more side effects, but we have a limited range of antibiotics and not all are effective against all bacteria, so there is not always a better antibiotic to give to a patient. As you can see, this is not a one-off problem, but a dynamic problem, the way we solve it now changes the way we will be able to solve it in the future, bacteria adapt to selection pressure and are able to exchange the information necessary to develop that resistance. They have many methods, they secrete substances that destroy antibiotics, they develop transporters that expel the antibiotic from their cells, or they simply secrete proteins that immobilise them. The point is that they have proven to have plenty of resources to combat antibiotic treatments. Moreover, the most wanted list has an ESKAPE name, listing the most dangerous pathogens that are multi-resistant to several, if not all, antibiotics.
Given this situation, and taking into account the multi-million dollar cost of developing a new antibiotic, is it worth continuing the development of antibiotics? as a long-term strategy, or whether the approach should be changed. Some candidates have been proposed as viable alternatives to the standard antibiotic strategy.
Quorum sensing
One of them is the Quorum Sensing, a communication system, mediated by chemical signals.between a population of bacteria of one or more species that they use to estimate their population density or where they are in the colonisation of an environment. In response to these stimuli, bacteria are capable of coordinating their dormancy statestress responses or toxin production. This opens a way for pathogenic bacteria to change their behaviour, either by mimicry or inhibition (like tapping into an enemy’s communications to impersonate a command to lower their weapons), by simply manipulating the concentration of a substance in the pathogen’s environment. The chemical signallers are the acyl-homoserine-lactones, small molecules that have an core common core that varies according to the bacteria The specific time period in which it is produced and it is characteristic of gram-negative bacteriawhile in gram-positive we found oligopeptides fulfilling this function. Although this system allows us to modulate virulence or toxin expression in bacteria, not all attack mechanisms are regulated by this system (the mere presence of gram-negative bacteria in body fluids already causes a non-specific immune response due to their membrane endotoxins) and is highly dependent on fine control of their concentration, This is difficult due to the constant metabolic dynamics and different permeabilities of tissues in the human body, and requires a thorough knowledge of the mechanisms regulating this system for each type of bacteria, whereas antibiotics act in a generic way against similar bacteria.
Phage therapy
Phage therapy consists of the use of active bacteriophages (virus which selectively infect bacteria) in order for them to destroy the population causing an infection, is the microbial equivalent of releasing a weasel to catch a snake. Bacteriophages can have a very high specificity and attack very specific strains of bacteria, as they recognise specific membrane proteins. This has both positive and negative aspects, for example, the ability to destroy the pathogen while leaving cells of the symbiotic microbiome or host organs intact, but on the other hand, this specificity can make the phage ineffective against a slightly different or less common strain of the bacterium it is expected to fight. A peculiarity of phages as a therapeutic agent, which may be the most relevant, is that it is an agent capable of evolving. We said above that the problem of antibiotic resistance was a dynamic problem, well, this may be a dynamic solution. Just as bacteria generate resistance to antibiotics through constant confrontations with them, phages also mutate and are able to adapt and outwit the defences that bacteria put up against them, such as the famous CRISPR. This system consists of a set of proteins and fragments of DNA which give rise to an immunological memory in bacteria of phages with which they or their predecessors have been infected and have managed to overcome, a very effective system but one that some phages still manage to circumvent. As a speculation, it may even be that a phage given to a patient to fight an infection may be strengthened by this process. On the other hand, although the specificity of phages gives good assurances that they will be harmless and will not cause host infection, the immune system is relentless and will seek out and destroy anything it does not recognise as its own, limiting the action of phages to the window of time from administration to the development of immunity to the phage. On the regulatory side, the introduction of an active virus in the organism The fact that it is not just a substance that always acts in the same way and whose purity is easily known, viruses by nature have a strong tendency to mutate and diversify, which makes it difficult to obtain a homogenous and reproducible product based on bacteriophages. The world’s leading institution in phage therapy development and advocacy is the ELIAVA institute in Georgia, which has a huge collection of phages that have been tested against the most common pathogenic bacteria.
Immunotherapy
The antibodiesas we have explained in previous posts on this blog, are proteins that function as a tool of the immune system.by participating in the identification and neutralisation of a pathogen. It is possible to manufacture these antibodies and indeed they form part of some antisera for clinical use, but a drug not only has to be effective for it to be a real solution, but it must also it must be feasible. The administration of antibodies as a drug to fight an infection against which antibiotics are ineffective is an obvious solution but may not be the most efficient. Antibodies have enormous pharmacological potential. and have undergone exponential development in recent decades, but the production of such a drug is extremely complex and expensive, and considering its use for treatment of common infections or even infections with non-severe complications would not be economically viable today. In the future, science may be boosted by the development of technologies that make this process substantially cheaper, but for the foreseeable future, this is not a solution.
Alternation in the use of antibiotics, therapeutic fallowing.
Antibiotic resistance is something that in bacteria can develop over several generations of exposure, or it can be acquired from other bacteria that have previously developed it in the form of plasmid resistance plasmid (a small circular DNA fragment containing the information needed to express resistance traits). The bacteria acquire and discard plasmids according to the selection pressure of their environment, since cells optimise the use of the available resources by conserving and fixing information genetics which is useful to them in general and discarding it when maintaining this ya does not give them an advantage (as when we learn to do integrals at school, at that moment we need them to pass the subject, we adapt and keep that ability for some time, but when there are no more subjects to pass and our mind is dedicated to other tasks, the ability to solve integrals disappears in a short time). When an antibiotic is used in large numbers over a long period of time, a selection pressure is exerted on the bacteria to be fought, and only those that are able to overcome the antibiotic in question will survive. If these bacteria fix the genetic information that confers resistance in the form of a plasmid, they will keep it for as long as this selection pressure exists, as it will continue to be useful to them. Other resistance genes for other antibiotics, virulence factors, enhanced regulatory mechanisms, etc. can be added to this plasmid, but as the use of the first antibiotic wears off, this plasmid will be replaced by a new one. gene will also disappear from bacterial populations. It is then, when the first antibiotic no longer exerts a selection pressure, that bacteria have lost resistance and this antibiotic becomes competent to fight infections again. This is easy to control in a laboratory when our host and bacterial population fits in a shoebox, but not so easy when we are talking about public health at the international level. A coordinated global public health strategy could be envisaged in which the use of specific antibiotics would be conditional on their microbial resistance status to generate vulnerability to an antibiotic. Indeed, some steps have already been taken in this direction by reducing the use of antibiotic-containing medicated feed for livestock, thereby reducing environmental exposure of bacteria to antibiotics that should be relegated to human clinical practice. But a rigid plan in this sense would be very difficult to harmonise, as industry, patients and administrations would have to agree that when the time comes, the distribution of specific antibiotics should be stopped and replaced by others, when this antibiotic could be in anyone’s medicine drawer and socially, it would be difficult to explain that you can no longer prescribe the antibiotic that was prescribed to your neighbour a month ago.
In summary, we could say that, although research gives us better tools every day to fight infections and other diseases, not everything can be entrusted to a state-of-the-art drug, our actions influence the prospects for community health.
Martín Perales
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