Antibiotic Resistance: The Next Challenges Facing Research

Science

Each year in France, 125,000 infections and 5,500 deaths can be attributed to antibiotic resistance. Faced with this major public health issue, a priority € 40 million research program coordinated by Inserm is being launched. Its objective? To fight this threat on all fronts.

To combat antibiotic resistance, the French Ministry of Higher Education, Research and Innovation is launching a € 40 million priority research program, the coordination of which has been entrusted to Inserm. It follows on from the interministerial roadmap established in 2016 to address this public health issue. A major challenge given that "according to a study by the European Centre for Disease Prevention and Control published last November (publi), 33,000 deaths in Europe were attributed to antibiotic resistance in 2015. Even more alarming, the burden is highest in children under the age of one and adults over the age of 65, and in five years’ time will be higher than that of Aids, tuberculosis and malaria combined!" , warns Evelyne Jouvin-Marche*, Deputy Scientific Director at the Inserm Immunology, Inflammation, Infectious Diseases and Microbiology theme-based institute. In addition, with its 5,500 annual deaths, France is the sixth most affected country in Europe. Hence the decision to intensify research against this threat.

But the battle promises to be complex. The main reason being that resistant bacteria are everywhere, in humans, animals and in the environment. Fighting antibiotic resistance requires a holistic approach, the aptly-named One Health. We are facing a number of challenges and in order to address them, the priority program has been broken down into four research orientations "which will be conducted simultaneously and across multiple sectors, i.e. in human health, animal health, the environment and in the human and social sciences, clarifies Jouvin-Marche. This multisectoral approach will also be one of the challenges of the program."

Increase our knowledge…

One of the orientations addresses the resistance itself, how it emerges, how it is transmitted and how it spreads. "This involves a wide variety of research, ranging from the genetics of resistance, the geographical and temporal monitoring of the resistance, the search for biomarkers of treatment efficacy, to the modeling of the transmission and emergence of the resistance...", states Marie-Cécile Ploy**, from the Genomics, Environment, Immunity, Health and Therapeutics Institute (GEIST) in Limoges and who is responsible for this orientation. With each theme generating large quantities of information, databases will be developed which everyone can access. "The objective is to facilitate access to knowledge, avoid doing the same work twice, and save time. For example, a team which identifies a mutation will quickly be able to find out whether this mutation is already known and whether it is associated with resistance, adds the microbiologist. Finally, and more broadly, we will look for a methodology according to which we can all work together, irrespective of our sector because we need to share the same vision, which isn’t easy."

… to defend ourselves more efficiently

Increasing our knowledge of resistance will help us develop new therapeutic strategies, which are the focus of the program’s second orientation. And here again, a multipronged approach is being taken. According to Bruno François*** from Limoges University Hospital, "at present, the most promising are immune stimulation making it possible to defend oneself against bacterial infection, and monoclonal antibodies". The latter block the virulence factors of the bacteria without destroying them. Several monoclonal antibodies are currently being evaluated in patients "and the initial results are encouraging, completes the doctor who specifies that vaccination also remains one of the most effective means of indirectly fighting bacteria".

To prevent infection and eliminate resistant bacteria, the microbiota could also be a valuable ally. The hundred thousand billion bacteria in our body form the primary barrier against their foreign counterparts, whether pathogenic or not. They starve them, produce natural antibiotics and stimulate the immune system. Hence the search for treatments to protect or manipulate the microbiota against the antibiotics likely to jeopardize it, or to reconstitute it through "cocktails" of bacteria, such as probiotics or fecal transplantation.

Another avenue to explore: the bacteriophages. The use of these bacteria-killing viruses was abandoned in favor of antibiotics, except in Russia and Georgia where they are still prescribed despite the lack of standardized scientific evaluations. "However, the studies on the microbiota and bacteriophages are making little progress", notes François. "But we should keep all our options open", adds Jouvin-Marche. That is why the development of new antibiotics also forms part of this research orientation. "For example, murepavadin is a very recent antibiotic against Pseudomonas [responsible for lung and urinary infections, and which has been designated a critical priority by the World Health Organization, Ed.], states François. However, given the ability of the bacteria to adapt, to me it appears more interesting to look for combinations of antibiotics or combinations of an antibiotic with an adjuvant, to boost treatment efficacy. And of course, more targeted use needs to be made of the existing treatments."

… and innovate better

"The third orientation of the priority research program concerns technological innovations such as big data and artificial intelligence", indicates Jouvin-Marche. As yet underdeveloped for the fight against antibiotic resistance, their potential leaves no doubt. In this way, diagnostic tests of bacterial infections and resistance, rapid and inexpensive, will make it possible to use the right antibiotic. "The new technologies will also make it possible to harness the data available on the bacteria and patients and therefore to test whether such and such an approach is appropriate, explains the immunologist. In addition, this information could incite manufacturers to invest in this combat."

Finally, this combat also involves good hygiene practices in healthcare facilities, and presents public-health, social, psychosocial, medico-economic and legal challenges. All of which come under the umbrella of the fourth orientation. "Studying these mechanisms, for example the cultural approaches to the use of antibiotics in human and animal health is very important because these are in a way the root of antibiotic resistance", emphasizes Jouvin-Marche.

There is no doubt that, with this ambitious program, France is fighting antibiotic resistance on all fronts. But the benefits do not end there. "France will gain visibility, even if it is already highly engaged at the European level through various programs including the Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EU-JAMRAI), emphasizes Jouvin-Marche. As for the funds invested, they will serve as a lever to find other sources of finance." Finally, "the program will oblige us to think differently and be inventive," concludes Ploy.

 

Notes:

* Unit Inserm 1209/Université Grenoble-Alpes/CNRS, Institute for Advanced Biosciences

** Unit 1092 Inserm/Université de Limoges/Limoges University Hospital, Antimicrobials: molecular supports of resistances and therapeutic innovations

*** CIC 1435 Inserm/Université de Limoges; Unit 1092 Inserm/Université de Limoges/Limoges University Hospital, Antimicrobials: molecular supports of resistances and therapeutic innovations