Antibiotic resistance: What innovations?

The World Health Organization (WHO) has released its new report on antibiotic resistance and it is worthy of attention. This rigorous study reminds us that this phenomenon of bacterial resistance causes about 480,000 cases of multi-drug resistant tuberculosis in the world every year and already leads to 700,000 deaths per year worldwide (including 25,000 in Europe). The WHO stresses that "Antimicrobial resistance is a global health emergency that seriously jeopardizes the progress of modern medicine".
Bwhile WHO refers to With 51 new antibacterial products in clinical development to treat priority antibiotic-resistant pathogens, she says that only eight of these treatments are truly innovative. In particular, the study highlights the lack of treatment options for resistant tuberculosis, which kills some 250,000 people a year, as well as for bacteria such as Acinetobacter or enterobacteria, such as E. coli, which cause serious and often fatal infections, especially in hospitals. Finally, the WHO points out that prevention and a much more rational use of antibiotics - for both humans and animals - are essential to curb this major threat to world public health.
Another study published three years ago by the British authorities estimates that microbial resistance to antibiotics could cause 10 million deaths per year worldwide in 2050 and reduce the Gross World Product by 3 %. If this grim scenario were to become reality, antibiotic resistance would become the leading cause of death in the world by mid-century, ahead of cancer, cardiovascular disease, diabetes and diarrhoeal diseases. The study states that the majority of these deaths would occur in Asia (4.7 million) and Africa (4.1 million), but our continent would not be spared, with about 390,000 deaths per year....
In France, it is estimated that resistant bacteria are responsible for more than 80 % of the 12,500 annual deaths by infection that occur in hospitals, according to a recent survey by Santé Publique France. These include species such as Escherichia coli and Klebsiella pneumoniaewhich belong to the WHO list of the 12 most threatening families of bacteria to human health. Most worryingly, however, the hygiene measures taken in hospitals, while they have reduced the number of patients infected with staphylococci, have had no effect on the spread of resistant enterobacteria.
Faced with this increasingly worrying medical and health situation, public research and private laboratories, after long neglecting research in this field, have intensified their efforts in recent years to offer patients new therapeutic solutions. More and more patients are falling victim to resistant bacteria.

Research around the world

Three years ago, a multidisciplinary Canadian research team from the Université de Sherbrooke, combining biology, microbiology, bioinformatics and chemistry, announced that it had discovered, after many years of research, a new class of antibiotics against the pathogen called Clostridium. This bacterium is the main cause of nosocomial diarrhea associated with antibiotic use in industrialized countries.
These researchers have been able to show the effectiveness of their molecules in a mouse model of infection and clinical trials on humans are underway. The operation of this new class of antibiotic is both simple and remarkable: it uses a molecule called PC1, discovered by these researchers, which has the property of being able to bind to the riboregulator, thus blocking the genes necessary for the bacterium's survival. This strategy will make it possible to lure the bacterium by giving it false information, ultimatelydestroy it.. "The potential of this new class of antibiotics is all the more promising because our molecules do not induce any resistance in bacteria, even after prolonged contact with the molecule, said Daniel Lafontaine, professor at the Faculty of Science at the Université de Sherbrooke.
A few months after this Canadian announcement, another American team from Northeastern University in Boston, led by Professor Kim Lewis, in turn identified a new antibiotic, teixobactin, which has been shown to be effective in mice to treat certain resistant strains of bacteria. These researchers were able to identify this substance by screening more than 10,000 compounds extracted from soil bacteria and cultivated according to a new method patented by the American pharmaceutical company NovoBiotic.
The first tests on mice have confirmed the effectiveness of this new antibiotic on resistant bacteria, such as Clostridium, which causes diarrhoea, Staphylococcus aureus, which causes food poisoning, and Staphylococcus aureus, which is a cause of food poisoning. Mycobacterium tuberculosis...the bacteria responsible for tuberculosis. This work showed that teixobactin killed the bacteria by causing the cell wall to break down, a mechanism similar to that of a well-known antibiotic, vancomycin.
In early 2017, a team of researchers led by Bruce Geller of Oregon State University announced the discovery of a molecule that reverses antibiotic resistance in several strains of bacteria. The molecule in question is a peptide that directly attacks the NDM-1 (New Delhi metallobêta lactamase) enzyme that confers resistance to carbapenem antibiotics, usually reserved for the treatment of multi-resistant infections.
Combined with meropenem, a type of carbapenem used to treat the urinary tract, this new molecule has made it possible to restore the ability of antibiotics to attack bacteria. Researchers were able to effectively treat infection by bacteria raised in Petri dishes and improve survival rates in infected mice. However, the exact therapeutic effectiveness of this new molecule will only be known once the results of human clinical trials are available.
It should also be noted that a new "composite" antibiotic is expected to be available in Europe in a few weeks' time. Called ZaviceftaThe first, avibactam, makes it possible to block the production of Beta-lactamases (BLs) in most multi-resistant enterobacteria, molecules that these bacteria use to render Beta-lactam antibiotics (penicillins, cephalosporins and carbapenems), the most widely prescribed antibiotics, ineffective. The second is the ceftazidime. Thanks to this synergistic combination, this new antibiotic manages to thwart bacterial resistance to this family of antibiotics in 80 % cases.
This summer, Brazilian researchers from the Centro Nacional de Pesquisa em Energia e Materiais (CNPEM) presented a new and innovative method to combat certain bacteria. It consists of coating nanoparticles composed of silver and silica with a layer of antibiotic. This research has shown that this coupling of chemical molecules and silver nanoparticles makes it possible to kill most resistant microorganisms. But many years of research and clinical trials in animals and then in humans are still needed to make this highly innovative therapeutic tool available in complete safety.
Another important discovery was announced last October by Italian researchers led by Professor Maffioli. These scientists have just discovered a new antibiotic called pseudouridimycin (PUM). This natural molecule, present in the soil, can kill a wide range of bacteria, particularly those known as gram-negative bacteria (see Cell). The first in vitro tests have shown that this substance destroys about twenty species of resistant bacteria, including streptococci and staphylococci.
Pseudouridimycin destroys these bacteria through an original mechanism that targets a key enzyme, polymerase. As a result, this substance significantly reduces the risk of the development of bacterial resistance. In passing, these researchers stress the importance of ensuring good preservation of the soil, which (as the recent discovery of teixobactin also shows) is a particularly rich reservoir of potential therapeutic substances.
Since pseudouridimycin belongs to the same family of molecules as the most effective drugs known for the AIDS and hepatitis C viruses - nucleoside analogues used for nucleic acid synthesis - the use of this new enzyme inhibition mechanism also opens the way to the development of a wide range of drugs that could be combined with other existing classes of antibiotics. Initial tests in mice have shown promise, and pseudouridimycin has been shown to cure, without toxic effects, mice infected with the dreaded Streptococcus pyogenes bacterium.
In parallel with therapeutic advances, science is also progressing, in terms of fundamental research, on the knowledge of the complex biological mechanisms that allow bacteria to develop resistance to antibiotics over time.
Earlier this year, American scientists at McMaster University examined a bacterium found 300 metres underground in the Lechuguilla Cave, the deepest cave in the United States. The bacterium, called Paenibacillus, is resistant to most of the antibiotics used today, including so-called "drugs of last resort" such as daptomycin. These microorganisms have been isolated from the outside world for more than four million years in the cave.
This research shows that the bacterium is resistant to 18 different antibiotics and uses defence methods identical to those of similar species found in soils. This discovery is important because it shows that evolutionary pressure seems to have preserved these resistance genes for millions of years - and not just since antibiotics have been used to treat infections. This work has also identified five new pathways that allow these bacteria to become resistant to all known antibiotics, which will allow researchers to anticipate and develop new drugs to fight this type of resistance before it occurs.
Also in early 2017, Chinese researchers have identified antibiotic resistance genes and modes of resistance transfer between species. This resistance is the result of an evolutionary process that follows the laws of natural selection. As a result, the bacteria most sensitive to antibiotics are eliminated, while those that have managed to make a life-saving mutation survive and can thus continue to reproduce and pass on their resistance genes to their offspring. Studies have also shown that these genes responsible for antibiotic resistance can, among other things, spread from one bacterial species to another, and can also be transmitted between farm animals and the human intestinal microbiota.
These Chinese researchers, confirming the major place they now occupy in the field of life sciences, have succeeded in identifying and describing this "mobile resistance" which would be largely responsible for the spread of antibiotic resistance. In particular, these researchers have identified 36 resistance genes that are common between the human intestinal microbiome and that of the hen. The study showed very interestingly that a large part of the transfer of resistomes takes place laterally, by horizontal gene transfer. In this process, an organism integrates genetic material from another organism without being a descendant.
Our country is also very involved in this research and, last April, while studying the intestinal microbiota, researchers from INRA and Inserm also made another very interesting discovery on the model bacterium Bacillus subtilis. Its genetic analysis revealed the presence of conserved genes in enterococci, common bacteria of the intestinal microbiota.
This work has made it possible to describe a new enzymatic mechanism capable of transforming a peptide into a bioactive molecule. Called epimerization, this enzymatic transformation leads to a molecular transformation of certain amino acids, according to a mechanism never seen before in living organisms. This is the first time that researchers have demonstrated in vitro the ability of certain enzymes to catalyze epimerization within a peptide.
Surprisingly, the modified peptide, known as an epipeptide, has been shown to be very effective in inhibiting the growth of Bacillus subtilis. These epipeptides thus represent a new class of natural products that could be used to develop new antibiotics against Gram-positive bacteria (such as staphylococci, enterococci or streptococci), whose increasing resistance to antibiotics is a serious problem.
It should also be noted that a few days ago, a team of researchers from the Department of Biochemistry and Molecular Medicine at the UdeM in Canada presented a new technique that could block the transfer of antibiotic resistance genes (See Nature). These researchers discovered how the transfer of plasmids (fragments of DNA) that allow certain genes to make bacteria resistant to antibiotics takes place. According to these scientists, it would be possible, using certain chemical molecules, to selectively block this plasmid transfer and thus prevent, "at the source", the development of this antibiotic resistance phenomenon.
But antibiotics as we have known them since 1928, thanks to Flemming, will perhaps give way, within ten years or so, to new revolutionary therapeutic tools currently under development and full of promise: éligobiotics. At any rate, this is the firm conviction of two brilliant young French researchers, Xavier Duportet and David Bikard, who in 2014 created the company Eligo Bioscience. They are working on a technology called "Eligo". The idea is to design new-generation antibiotics capable of targeting a specific bacterium on demand, without affecting the surrounding microbial life. These elobiotics use the famous CRISPR genetic editing tool to locate with absolute precision the specific DNA sequences of resistant bacteria. Eligobiotics will then come and destroy only these sequences, which will lead to the death of the targeted bacteria, without disturbing the patient's microbiome. Initial tests on mice have shown that these elegobiotics can indeed effectively destroy resistant bacteria of the Staphylococcus aureus family and Escherichia coli without affecting the surrounding bacteria.

Reducing our consumption of antibiotics

As we can see, all of these discoveries, both in terms of basic research and therapy, make us reasonably optimistic and may perhaps, if we maintain our efforts in this crucial area of bacterial resistance, avoid the realization of the WHO disaster scenario.
But I want to reiterate strongly that all these medical and scientific advances alone will not be enough to meet the major global health challenge posed by the growing number of resistant bacteria. If we really want to get to the root of this huge problem, we must also make profound changes in the way we use antibiotics and succeed in drastically limiting their use and restricting it only to those medical situations that require it and must remain exceptional.
The latest report from the ANSM (Agence Nationale de Sécurité du Médicament), tells us that in 2015, 786 tons of antibiotics were sold in France for use in human health, which corresponds to 29.9 doses per 1,000 inhabitants per day. This consumption has not decreased over the last ten years and remains 36 % higher than the European average.
This study confirms that France, the third largest consumer of antibiotics in the European Union behind Greece and Romania, remains one of the countries with the highest consumption of antibiotics in Europe. If we now compare the average per capita consumption of antibiotics between France and the most virtuous European countries - Germany, Sweden and the Netherlands - we can see that each French person consumes, on average, twice as much antibiotics as a German, a Dane or a Swede...The result of this disparity in the use of antibiotics is that, in those northern European countries that have learned to use antibiotics wisely, the number of resistant bacteria, nosocomial infections and deaths due to these pathogens has decreased very significantly....
We must therefore immediately follow the example of our Nordic neighbours to radically change - both doctors and patients - their attitude to antibiotics and prescribe them much more selectively. In this respect, the shared digital medical record, which is finally coming into place, can provide our health system with a new and valuable tool for assessing and forecasting drug consumption in general and antibiotic consumption in particular. We could start by setting ourselves a precise and ambitious objective: to halve the overall consumption of antibiotics in France within five years.
Let us hope that our country finally becomes aware of this recurring problem, which is at once scientific, medical, social and cultural.
René TRÉGOUËT, Honorary Senator - Founder of the Senate Foresight Panel
The original of this article was published in RT Flash, 12/01/2018

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