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RESEARCH – To avoid losing the fight against the loss of efficacy of antibiotics, international research is considering several strategies, all different as complementary.
A disturbing inventory
Every year in France, nearly 13,000 people die from an infection caused by bacteria that have become multi-resistant to antibiotics, that is to say as much as deaths related to diseases or heart and vascular accidents. On a global scale, this number now exceeds 700,000. According to serious estimates, it could reach 10 million in the next 30 years
Weapons used for nearly a century in the fight against pathogenic bacteria, antibiotic molecules are unfortunately less and less effective. The fault lies in the very mechanisms that govern the evolution of life. Indeed, when bacteria proliferate, they do not necessarily reproduce identically. At random, mutations (or borrowing from neighboring bacteria) give them properties that may prove advantageous in the face of an antibiotic. If all their congeners are decimated by an antibiotic, and these isolated strains will have the free field to found a dynasty that will be precisely indifferent to this treatment.
That's why the more we use antibiotics, the less effective they are. We need to learn to fight these pathogens differently.
Six strategies to consider
To avoid losing the fight, multiply strategies is essential. Beyond the necessary sensitization of doctors, veterinarians and the general public to the "good uses" of these drugs (relevant situations, useful doses, duration of use …), solutions are being studied in laboratories . The most promising avenues were detailed by Brigitte Gicquel, Head of the Mycobacterial Genetics Unit at the Pasteur Institute, and Bruno François, Coordinator of the Inserm Clinical Investigation Center at the University Hospital of Limoges.
Strategy n ° 1: expand the arsenal
Strategy 2: Less powerful but better targeted strikes
Strategy # 3: Sabotage Shields
Strategy # 4: let it proliferate, but make it harmless
Strategy # 5: Quickly occupy the field with harmless bacteria
Strategy # 6: Enlist Viruses for Surgical Strikes
Strategy # 1: Expanding the arsenal …
Continuing use of the same antibiotics increases the likelihood of emerging bacteria that are resistant to them. We must find new recruits. Several laboratories around the world are seeking to identify new molecules capable of targeting the most dangerous bacterial strains.
Technology is helping researchers: to determine which molecule can interact with which bacterium (s), we let robots perform the tests for us. This is the method of "high throughput screening," which allows the evaluation of hundreds of thousands of combinations, and the discovery of some candidates for testing in vivo. "Until now, with this method, we found some antibiotics, but they are not revolutions," says Brigitte Gicquel.
According to her, other avenues of research are "promising": "rather than simply identifying molecules that kill bacteria, some researchers are trying to understand how they kill, if we dissect the mechanisms of action, if we understand how the antibiotic alters the metabolism of the bacterium, we precisely identify targets, before starting to look for molecules [qui pourront interagir avec elles]. "
… while empowering the uses
However, according to the researcher, "discovering new antibiotics is not an issue to be considered in isolation": we must not waste this resource. "When researchers discover a better molecule, a strong publicity is made by the industry to convince doctors to use this product," says Brigitte Gicquel. "This pressure, put in the few years the manufacturer has the exclusivity of the molecule, makes the new antibiotics are used indiscriminately, favoring the selection of resistance … This will literally" kill "this new molecule, and make it inoperative ".
"It is absolutely necessary to leave this logic, otherwise we will not have antibiotics which will have a utility on the long term", deplores it. "Financing the search for molecules only makes sense in a context where everyone acts responsibly."
Leaving this vicious circle, however, appears difficult, the pressure for a return on investment being set even though antibiotics bring little money to industry "especially because they are short-term treatments, or that these drugs target diseases that affect people who can not buy them very expensive, "says Brigitte Gicquel. The problem of antimicrobial resistance therefore has "a strong economic component", she explains, "[puisque] there is no point in discovering a molecule that no industrialist will want to produce ".
See also: A new antibiotic is exciting the world of research
Strategy 2: Less powerful but better targeted strikes
To limit the risk of developing resistant bacteria, it is necessary to minimize the situations in which an antibiotic used against a given infection comes into contact with little or no offensive bacteria. Many initiatives could deliver the relevant drug as close as possible to pathogens for the shortest period of time.
Dr. Bruno François considers "very important" recent advances in the field of diagnostics, "which identify, almost in real time, the pathogens responsible for infections". "The idea is to better target treatments, and avoid systematic use of broad-spectrum antibiotics" – which eliminate many non-resistant bacteria, whether or not they are involved in the infection.
The problem must also be considered in its temporal dimension. "Take for example the case of tuberculosis", illustrates Brigitte Gicquel. "We would like to understand why after two months, if we stop treatment, about 60% of patients are cured and 40% are not, and we know that some people have" dormant "bacilli, which remain in certain cells … We must deepen our understanding of these differences, because to treat a patient two months or six months, it is not the same, in particular concerning the risk of appearance of bacteria resistances. " Hence the importance of studying immunological markers indicating when it is appropriate to stop treatments.
Antibiotics on a commando mission?
In the idea of always better targeting treatments, several research teams – including one collaborated by the researcher of the Institut Pasteur – are studying the means of transporting the treatments "as close to pathogens in the body".
"We develop nanoparticles that will somehow" encapsulate ", totally or partially, the antibiotic molecules". This can release the antibiotic delayed in the body, limiting the risk that it is degraded before reaching its target, "and thus reduce the doses administered. But this is not the most ambitious goal of this technology.
"Some of these nanoparticles have the ability to stick to cells, depending on specific markers present on their surface.They will come closer to either bacteria or infected cells, or to gather in certain organs. to limit as much as possible [les interactions avec d’autres bactéries présentes dans l’organisme]"Although the technique is already used in oncology, it is still far from a marketing of antibiotics." Results were recently obtained in the laboratory (against tuberculosis bacilli and streptococci resistant to meticillin ", says Brigitte Gicquel, while recalling the many progress that remains to be accomplished." It is not yet known how to "encapsulate" all antibiotics, especially because of the size of the molecules. Similarly, it must be ensured that the antibiotic remains effective as long as it has not been delivered … "
Koch bacilli (Mycobacterium tuberculosis), bacteria responsible for tuberculosis.
Strategy # 3: Sabotage Shields
The resistances acquired by the bacteria during the mutations can be of various types: thicker cell wall, mechanisms for rejecting molecules intruded out of the cell, etc. Many research teams are working to inhibit these mechanisms of resistance using ancillary treatments, in order to allow antibiotics to be able to penetrate the bacteria and make their office.
"Many resistances are linked to enzymes, beta-lactamases, which degrade the antibiotic before it acts," says Bruno François. "Many pharmaceutical companies are now looking for molecules that can inhibit these enzymes."
Both researchers find these approaches "very interesting". "It's very concrete, and there are already a number of inhibitors that are in the industrial development phase," said Brigitte Gicquel.
See also: Discovery of an unprecedented and promising antibiotic process
Strategy # 4: let it proliferate, but make it harmless
The previous strategies are not, strictly speaking, alternatives to antibiotics, but rather ways of optimizing their use. "Alternatives? Yes, there are some credible," explains Bruno François.
"Among the most promising approaches are undeniably the use of anti-infectious monoclonal antibodies," explains the head of CIC Limoges. Unlike an antibiotic that will kill a bacterium, "the monoclonal antibody will target receptors, on the surface of the bacteria, badociated [à la production ou à la sécrétion] substances that are dangerous for the host organism. It is, in short, to "disarm" the bacterium, which remains present but is no longer incapable of being infectious.
Not insignificant advantage of this approach: unlike antibiotic treatments that are clear for resistant bacteria, these molecules do not contribute to select resistant strains.
Treatments already under development
"Some anti-infectious monoclonal antibodies are already on the market, especially against Clostridium difficile", says Bruno François, adding that other promising candidates are in clinical trials." Some have already been tested on healthy volunteers and sick people, for example in the case of infection. Staphylococcus aureus (Staphylococcus aureus) or Pseudomonas aeruginosa. Other molecules are about to be tested, especially against Escherichia coli ou Klebsiella pneumoniae. At the current rate, it is not excluded that some of these treatments come on the market in the next 4 or 5 years."
Like monoclonal antibodies already used in oncology or against certain autoimmune diseases, these treatments are administered intravenously. Bruno François finally notes that, like the antibodies produced by our own body, these therapeutic molecules "persist for a long time in the body before being eliminated", thus offering patients "protection that will last for several months, with a single injection" .
Culture of Staphylococcus aureus (Cc-by-sa HansN)
Strategy # 5: Quickly occupy the field with harmless bacteria
The bacteria that threaten us do not necessarily come from outside … and may already be in our mouths or intestines. We carry many bacteria that are potentially dangerous for certain parts of our body, but without deleterious effects in the areas where they are confined. This is especially true in the intestine, where many species of bacteria coexist and compete. That a powerful antibiotic pbades by, and the small antibio-resistant groups will be able to multiply … unless one repeuple very quickly the zone with the species of origin.
"This is called the transplantation of flora, with a reintroduction into the intestine of bacteria recovered in the stool of the patient before the use of the antibiotic, and then cultured," says Bruno François, referring to several tests in this direction conducted, particularly in France, in cancer services. "It remains, however, difficult to estimate the impact that this has, concretely, in terms of the fight against the proliferation of antibacterial bacteria".
Bruno François finally notes the existence of research concerning certain antibiotics intended to act on the level of the small intestine, against the Clostridium difficile. "A French company, Da Volterra, has developed an interesting method to inactivate the residual molecules before they arrive in the colon, which allows, among other things, to prevent these antibiotic residues from favoring the selection, and therefore the development. , bacteria resistant to the colon. "
Clostridium difficile observed by electron microscopy
Strategy # 6: Enlist Viruses for Surgical Strikes
Some viruses are capable of infecting and destroying bacteria: they are "bacteriophage" (or "phage") viruses. The idea of using them routinely to eliminate pathogens resistant to antibiotics is tempting … However, this track seems not promising to specialists.
"Many hopes have been put in these bacteriophages, but it's a bit like a" sea snake "", laments Bruno François. "They are anti-infective agents that have been used for a very long time in some Eastern countries, but their effectiveness and safety have not been truly scientifically evaluated.The few experiments conducted according to international standards are not extremely convincing. We need to continue research – some laboratories are working on this subject in France – but today we put little means on it.Therefore it is not a solution likely to arrive in the short term on the market, at least for mbad use ".
Brigitte Gicquel is equally pessimistic. "The problem is that the bacteria targeted by the viruses evolve … Very quickly appear mutations that make them resistant to phages, so this track is not, in my opinion, very promising. and ensure the quality of the phages that would be produced [à des fins thérapeutiques] seems to me very difficult.
Representation of a bacteriophage on the surface of a bacterium
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