Hygiene, prevention and surveillance have helped to reduce antibiotic resistance in several countries. However, it seems that these measures alone cannot completely contain antimicrobial resistance in its entirety. Other alternatives must be supported to control and reduce antibiotic resistance. Whether in human, animal or environmental health, there is a need for research to acquire new knowledge and to understand the host, pathogen and treatment mechanisms that contribute to the emergence of bacterial resistance, its transmission and dissemination in all ecosystems. The knowledge front should make it possible to understand all the underlying mechanisms that make, for example, a bacterial infection resistant to antibiotic treatment, and to elucidate why certain patients, at high risk of infection during hospitalization, do not become infected.<\/p>\n\n\n\n
In short, we need to investigate all host mechanisms, including immune, genetic, nutritional and psychological status, which make the host robust or vulnerable to bacterial infection, in order to propose a more effective therapeutic treatment and avoid selective pressure. On the bacterial side, the challenge is to understand all the mechanisms by which bacteria escape from current treatments and alternatives. It is important to know the biology of bacteria in order to find new therapeutic targets, and to understand how multi-resistant bacteria emerge, resist their environment, multiply and persist via reservoirs, and spread to different hosts and the environment.<\/p>\n\n\n\n
Support for research must include the development of new molecules, without creating resistance, to avoid therapeutic impasse, as well as new detection tools and early diagnostic tests to stop bacterial colonization as early as possible at host level, at population level (human and animal) to delay possible epidemics, and to control environmental reservoirs. This will make it possible to monitor the global evolution of resistance via standardized, shared and exploitable indicators (notably by taking advantage of the latest technological advances such as artificial intelligence) in all ecosystems. It is also crucial to develop research activity in the human and social sciences, in epidemiology and for interventional studies, in order to describe, analyze and understand the perception of the risk of antibiotic resistance, and to raise awareness among all healthcare professionals and users of the responsible use of antibiotics.<\/p>\n\n\n\n
These different fields of investigation – fundamental, clinical, innovative and societal – must be supported at the heart of a single research program, which must also address the challenges posed by antibiotic resistance in countries with limited resources, given the impact of globalization on this issue. An interdisciplinary program bringing together communities of scientists from different backgrounds, some of whom have not yet included antimicrobial resistance in their priorities, would be a real lever for cross-fertilizing skills and expertise to open up unexplored avenues of research and meet the need for innovations, alternatives and technological and behavioral breakthroughs.<\/p>\n\n\n\n
The interconnection of disciplines working on a common program would be an asset for boosting research on antibiotic resistance, supporting bold research with controlled risks, broadening the current fields of investigation of academic research and finding opportunities to secure funding to continue the research already underway.<\/p>\n\n\n\n
<\/p>\n\n\n\n
The 4 pillars of the Antibioresistance PPR<\/h2>\nThe priority research program on antibiotic resistance is based on four interdisciplinary and interconnected pillars:<\/p>\n\n\n\n
<\/p>\n\n\n
\n![\"\"](\"https:\/\/ppr-antibioresistance.inserm.fr\/wp-content\/uploads\/2020\/07\/schema-4-axes-objectifs_fr.png\")
<\/figure><\/div>\n\n\nFor each axis, the context, issues and research priorities are described, along with an action plan comprising 18 objectives, 53 actions and their indicators. Taken as a whole, the issue of antimicrobial resistance would require a denser program of actions in terms of number of objectives and complexity. It seemed more appropriate to the expert committee to focus solely on antibiotic resistance. To ensure that the RPP remains open-ended and is able to take account of new research and public health issues over the next 10 years, the Scientific Committee, Inserm and its partners recommend that the overall program presented in 2019 should be able to evolve and contribute to supporting challenges that have not yet been identified, depending on the success or otherwise of the challenges that will be undertaken.<\/p>\n\n\n\n
<\/div>\n\n\n\n\u203a 4 axes \u203a 18 objectifs \u203a 53 actions<\/strong><\/div>\n\n\n\n<\/div>\n\n\n\n<\/p>\n<\/div><\/div>\n\n\n\n
<\/div>\n\n\n\n\nFocus 1 \u2022 Emergence, transmission and dissemination of resistance<\/h2>\n\n\nContext<\/h3>\nAntibiotics are most often derivatives of natural compounds found in the environment, with their own metabolism. Antibiotic resistance is also a natural process that preceded their use by humans. The use of antibiotics, antiseptics and disinfectants on a bacterial species leads to the selection of resistant mutants that are able to multiply in the presence of these anti-infective agents. The phenomenon of selecting resistant variants to anti-infective agents following exposure exists in microbiology for all organisms, whether bacteria, viruses, fungi or parasites. The same is true of cytotoxic agents used in chemotherapy or insecticides used in vector control. Certain concepts of progressive selection of variants that escape treatment and their dissemination are common to these processes. However, the selection and transmission of bacterial resistance to antibiotics present two particularities that make their dynamics particularly complex. Firstly, these treatments will also affect human and animal microbiota, as well as microbial communities in the environment, by modifying their composition and selecting resistant strains which can then spread to other reservoirs. In addition, an important component of resistance results from the acquisition of resistance genes (ARGs) encoding efflux pumps or enzymes which, for example, inactivate an antibiotic, or modify its target. These resistance genes are frequently carried by plasmid or integrative mobile genetic elements (MGEs), which have the ability to pass from one bacterium to another within the same species, or between species that are even phylogenetically distant. The selection (emergence), transmission and dissemination of antibiotic resistance therefore involve not only the circulation of strains, but also that of EGMs in the multiple reservoirs constituted by human, animal and environmental populations under multiple evolutionary pressures.<\/p>\n<\/div><\/div>\n<\/div>\n\n\n\n
\nIssues<\/h3>\nAntibiotic resistance represents a major public health issue for both humans and animals. Surveillance networks<\/a> exist at multiple levels: national, with Sant\u00e9 publique France for human health, via the CNRs, ONERBA and the national missions of the CPIASs, and ANSES for animal health and the environment; international, with the WHO, OIE and ECDC in particular; but also at local level, at the level of a healthcare establishment. Antibiotic consumption by humans and animals and their release into the environment are also monitored. Alongside these surveillance activities, which are essential for identifying epidemiological changes in time and space, understanding the mechanisms of selection, transmission and dissemination of resistance requires a combination of approaches: i) an evolutionary approach to the selection dynamics of treatment-resistant strains capable of dissemination (and therefore of low biological cost), ii) a molecular approach to understand the mechanisms of acquisition and transfer of resistance genes and mutations, and iii) an ecological approach to understand and model the spatial interactions between microbiota and the intermittent selection pressures to which bacteria are subjected.<\/p>\n\n\n\nA key challenge for the future is to integrate innovative approaches into these studies to gain a detailed understanding of the processes involved (see also axis 3<\/a>): \u201comics\u201d approaches (genomics, metagenomics, transcriptomics, proteomics, and also metabolomics), \u201csingle cell\u201d or \u201csingle molecule\u201d studies, new imaging methods and mathematical and computational approaches, particularly learning approaches.<\/p>\n\n\n\nA second challenge will be to use mathematical tools to combine surveillance data and mechanistic knowledge to model the processes involved in the selection and dissemination of antibiotic-resistant strains and resistance genes in humans, animals and the environment. These models will make it possible to assess and predict the level of risk of acquisition and transmission of antibiotic resistance, associated with local or national antibiotic use policies, preventive healthcare measures, animal husbandry and water treatment procedures.<\/p>\n<\/div><\/div>\n<\/div>\n<\/div>\n\n\n\n
Research priorities<\/h3>\nSelection of resistance genes, resistant strains and resistance mechanisms<\/h4>\n\n\n\n
The emergence of a resistant clone is a complex process that combines four components that must be studied together:<\/p>\n\n\n\n
\n- Resistance genes and mechanisms: the first step in the selection of a new resistance mechanism is the capture of resistance genes in environmental reservoirs that are often little explored. Paradoxically, the environmental origin of major circulating resistance genes is still unknown. Once captured, resistance genes will have variable potential to evolve to target new antibiotics.<\/li>\n<\/ul>\n\n\n\n
\n- Chromosomal mutations: the selection of resistant strains also proceeds through the acquisition of mutations (SNPs, indels, recombination, amplification) in various systems directly or indirectly involved in the mode of action of an antibiotic or its accumulation in the bacterium.<\/li>\n<\/ul>\n\n\n\n
\n- The phenomena of persistence, tolerance and dormancy must be taken into account in the emergence and selection of resistant clones. These phenomena are under the control of genetic determinants that are still largely unknown, and are preliminary stages in the acquisition of mutations conferring resistance.<\/li>\n<\/ul>\n\n\n\n
\n- The selection and amplification of a resistant strain will depend on the selection pressure exerted by antibiotics and by numerous other molecules and\/or non-medicinal practices with a synergistic effect. This collateral selection pressure is often poorly understood, particularly for bacterial populations not directly targeted by treatment (species colonizing microbiota) or in the environment.<\/li>\n<\/ul>\n\n\n\n
Consequently, it is necessary not only to go beyond the catalog of these genes and mutations, but also to integrate the observations into a complex model to reconstruct the dynamics of the appearance of resistant clones and the underlying molecular mechanisms in terms of mutation selection, capture and transfer of resistance genes, and to identify the constraints involved in the success of a resistant clone, such as the compatibility of acquired resistance genes or EGMs with a genetic background, and in the successive acquisition of resistance genes, plasmids and mutations.<\/p>\n\n\n\n
Dissemination and transfer of clones and genes – reservoirs<\/h4>\n\n\n\n
Molecular epidemiology describes, for different species of pathogenic bacteria, the existence of dominant antibiotic-resistant clones and resistance genes associated with EGMs, as well as their distribution in different human, animal and environmental reservoirs. The population size of these clones can vary in time and space, on a local, national or international scale. The reasons for the \u201csuccess\u201d of these clones are still largely unknown, as are the reasons for their disappearance. Genomic sequencing and international cooperation should make it possible to identify these clones for major pathogenic species, as well as their circulation and geographical distribution in a \u201cOne Health\u201d dimension.<\/p>\n\n\n\n
The properties of these clones and the genetic determinants involved in their ability to disseminate and transmit between reservoirs are very diverse. They include the ability to colonize and persist in humans and animals or in the environment, resistance to stress, interactions with the host microbiota, and for EGMs carrying resistance genes, their capacity for intra- and inter-species transfer. The acquisition of resistance usually has a biological cost, and the ability to disseminate implies reducing this cost.<\/p>\n\n\n\n
Epidemic clones selected by these processes may have particular virulence properties (hyper- or hypo-virulence) which affect the risk associated with these clones and need to be better understood to be taken into account in diagnosis and surveillance. Resistant clones are intermittently subjected to selection pressure by antibiotics or antiseptics, often at low (sub-inhibitory) doses. They are also subject to host defenses (innate immunity, acquired immunity and vaccines) and environmental resilience. It is the result of these evolutionary and ecological constraints, and a clone’s ability to adapt, that determine the dynamics of resistant bacterial populations.<\/p>\n\n\n\n
<\/p>\n<\/div><\/div>\n\n\n\n
\nObjectives and action plan<\/h3>\n\n\n\nObjective 1 –<\/strong> To map the biodiversity of antibiotic resistance in the three Human-Animal-Environment (HAE) sectors and characterize the intra- and inter-sector transmission routes, as well as the bacterial and environmental factors involved in transmission.<\/h4>\nAction 1:<\/strong> We will set up hospital, community, animal health and environmental study sites (based in particular on existing workshop sites) enabling us to develop different research programs in environments monitored over time and space. These studies may include interventional study designs.<\/p>\n\n\n\nAction 2:<\/strong> By interacting with surveillance organizations in the human (Sant\u00e9 publique France), animal (ANSES) and environmental (AFB, INERIS) fields, we will set up methodological research to optimize the collection of surveillance data on antibiotic resistance and antibiotic consumption, as well as the collection and conservation of bacterial strains. The aim will be to better integrate data from the three sectors in order to characterize emergence and transmission pathways.<\/p>\n\n\n\nAction 3: <\/strong>Antibiotic resistance is a global issue, with the worldwide circulation of BMR and resistance genes via various genetic elements. We will encourage collaboration within international networks and analysis of the impact of international trade. Partnerships with low- and middle-income countries will be particularly encouraged.<\/p>\n\n\n\nAction 4:<\/strong> We will create a one-stop shop for biobanks of bacterial strains, particularly BMR, genetic supports and resistance vectors. We will develop \u201comics\u201d databases (complete bacterial genomes, resistome, metagenomic data from complex matrices – human or animal tissues or biological fluids, environmental matrices – transcriptomic and metabolomic data, etc.) from the three HAE ecosystems, which will be accessible for research purposes, taking into account all confidentiality constraints (in collaboration with axis 3<\/a>).<\/p>\n\n\n\n
The priority research program on antibiotic resistance is based on four interdisciplinary and interconnected pillars:<\/p>\n\n\n\n
<\/p>\n\n\n
<\/figure><\/div>\n\n\nFor each axis, the context, issues and research priorities are described, along with an action plan comprising 18 objectives, 53 actions and their indicators. Taken as a whole, the issue of antimicrobial resistance would require a denser program of actions in terms of number of objectives and complexity. It seemed more appropriate to the expert committee to focus solely on antibiotic resistance. To ensure that the RPP remains open-ended and is able to take account of new research and public health issues over the next 10 years, the Scientific Committee, Inserm and its partners recommend that the overall program presented in 2019 should be able to evolve and contribute to supporting challenges that have not yet been identified, depending on the success or otherwise of the challenges that will be undertaken.<\/p>\n\n\n\n
<\/p>\n<\/div><\/div>\n\n\n\n
Focus 1 \u2022 Emergence, transmission and dissemination of resistance<\/h2>\n\n\nContext<\/h3>\nAntibiotics are most often derivatives of natural compounds found in the environment, with their own metabolism. Antibiotic resistance is also a natural process that preceded their use by humans. The use of antibiotics, antiseptics and disinfectants on a bacterial species leads to the selection of resistant mutants that are able to multiply in the presence of these anti-infective agents. The phenomenon of selecting resistant variants to anti-infective agents following exposure exists in microbiology for all organisms, whether bacteria, viruses, fungi or parasites. The same is true of cytotoxic agents used in chemotherapy or insecticides used in vector control. Certain concepts of progressive selection of variants that escape treatment and their dissemination are common to these processes. However, the selection and transmission of bacterial resistance to antibiotics present two particularities that make their dynamics particularly complex. Firstly, these treatments will also affect human and animal microbiota, as well as microbial communities in the environment, by modifying their composition and selecting resistant strains which can then spread to other reservoirs. In addition, an important component of resistance results from the acquisition of resistance genes (ARGs) encoding efflux pumps or enzymes which, for example, inactivate an antibiotic, or modify its target. These resistance genes are frequently carried by plasmid or integrative mobile genetic elements (MGEs), which have the ability to pass from one bacterium to another within the same species, or between species that are even phylogenetically distant. The selection (emergence), transmission and dissemination of antibiotic resistance therefore involve not only the circulation of strains, but also that of EGMs in the multiple reservoirs constituted by human, animal and environmental populations under multiple evolutionary pressures.<\/p>\n<\/div><\/div>\n<\/div>\n\n\n\n
\nIssues<\/h3>\nAntibiotic resistance represents a major public health issue for both humans and animals. Surveillance networks<\/a> exist at multiple levels: national, with Sant\u00e9 publique France for human health, via the CNRs, ONERBA and the national missions of the CPIASs, and ANSES for animal health and the environment; international, with the WHO, OIE and ECDC in particular; but also at local level, at the level of a healthcare establishment. Antibiotic consumption by humans and animals and their release into the environment are also monitored. Alongside these surveillance activities, which are essential for identifying epidemiological changes in time and space, understanding the mechanisms of selection, transmission and dissemination of resistance requires a combination of approaches: i) an evolutionary approach to the selection dynamics of treatment-resistant strains capable of dissemination (and therefore of low biological cost), ii) a molecular approach to understand the mechanisms of acquisition and transfer of resistance genes and mutations, and iii) an ecological approach to understand and model the spatial interactions between microbiota and the intermittent selection pressures to which bacteria are subjected.<\/p>\n\n\n\nA key challenge for the future is to integrate innovative approaches into these studies to gain a detailed understanding of the processes involved (see also axis 3<\/a>): \u201comics\u201d approaches (genomics, metagenomics, transcriptomics, proteomics, and also metabolomics), \u201csingle cell\u201d or \u201csingle molecule\u201d studies, new imaging methods and mathematical and computational approaches, particularly learning approaches.<\/p>\n\n\n\nA second challenge will be to use mathematical tools to combine surveillance data and mechanistic knowledge to model the processes involved in the selection and dissemination of antibiotic-resistant strains and resistance genes in humans, animals and the environment. These models will make it possible to assess and predict the level of risk of acquisition and transmission of antibiotic resistance, associated with local or national antibiotic use policies, preventive healthcare measures, animal husbandry and water treatment procedures.<\/p>\n<\/div><\/div>\n<\/div>\n<\/div>\n\n\n\n
Research priorities<\/h3>\nSelection of resistance genes, resistant strains and resistance mechanisms<\/h4>\n\n\n\n
The emergence of a resistant clone is a complex process that combines four components that must be studied together:<\/p>\n\n\n\n
\n- Resistance genes and mechanisms: the first step in the selection of a new resistance mechanism is the capture of resistance genes in environmental reservoirs that are often little explored. Paradoxically, the environmental origin of major circulating resistance genes is still unknown. Once captured, resistance genes will have variable potential to evolve to target new antibiotics.<\/li>\n<\/ul>\n\n\n\n
\n- Chromosomal mutations: the selection of resistant strains also proceeds through the acquisition of mutations (SNPs, indels, recombination, amplification) in various systems directly or indirectly involved in the mode of action of an antibiotic or its accumulation in the bacterium.<\/li>\n<\/ul>\n\n\n\n
\n- The phenomena of persistence, tolerance and dormancy must be taken into account in the emergence and selection of resistant clones. These phenomena are under the control of genetic determinants that are still largely unknown, and are preliminary stages in the acquisition of mutations conferring resistance.<\/li>\n<\/ul>\n\n\n\n
\n- The selection and amplification of a resistant strain will depend on the selection pressure exerted by antibiotics and by numerous other molecules and\/or non-medicinal practices with a synergistic effect. This collateral selection pressure is often poorly understood, particularly for bacterial populations not directly targeted by treatment (species colonizing microbiota) or in the environment.<\/li>\n<\/ul>\n\n\n\n
Consequently, it is necessary not only to go beyond the catalog of these genes and mutations, but also to integrate the observations into a complex model to reconstruct the dynamics of the appearance of resistant clones and the underlying molecular mechanisms in terms of mutation selection, capture and transfer of resistance genes, and to identify the constraints involved in the success of a resistant clone, such as the compatibility of acquired resistance genes or EGMs with a genetic background, and in the successive acquisition of resistance genes, plasmids and mutations.<\/p>\n\n\n\n
Dissemination and transfer of clones and genes – reservoirs<\/h4>\n\n\n\n
Molecular epidemiology describes, for different species of pathogenic bacteria, the existence of dominant antibiotic-resistant clones and resistance genes associated with EGMs, as well as their distribution in different human, animal and environmental reservoirs. The population size of these clones can vary in time and space, on a local, national or international scale. The reasons for the \u201csuccess\u201d of these clones are still largely unknown, as are the reasons for their disappearance. Genomic sequencing and international cooperation should make it possible to identify these clones for major pathogenic species, as well as their circulation and geographical distribution in a \u201cOne Health\u201d dimension.<\/p>\n\n\n\n
The properties of these clones and the genetic determinants involved in their ability to disseminate and transmit between reservoirs are very diverse. They include the ability to colonize and persist in humans and animals or in the environment, resistance to stress, interactions with the host microbiota, and for EGMs carrying resistance genes, their capacity for intra- and inter-species transfer. The acquisition of resistance usually has a biological cost, and the ability to disseminate implies reducing this cost.<\/p>\n\n\n\n
Epidemic clones selected by these processes may have particular virulence properties (hyper- or hypo-virulence) which affect the risk associated with these clones and need to be better understood to be taken into account in diagnosis and surveillance. Resistant clones are intermittently subjected to selection pressure by antibiotics or antiseptics, often at low (sub-inhibitory) doses. They are also subject to host defenses (innate immunity, acquired immunity and vaccines) and environmental resilience. It is the result of these evolutionary and ecological constraints, and a clone’s ability to adapt, that determine the dynamics of resistant bacterial populations.<\/p>\n\n\n\n
<\/p>\n<\/div><\/div>\n\n\n\n
\nObjectives and action plan<\/h3>\n\n\n\nObjective 1 –<\/strong> To map the biodiversity of antibiotic resistance in the three Human-Animal-Environment (HAE) sectors and characterize the intra- and inter-sector transmission routes, as well as the bacterial and environmental factors involved in transmission.<\/h4>\nAction 1:<\/strong> We will set up hospital, community, animal health and environmental study sites (based in particular on existing workshop sites) enabling us to develop different research programs in environments monitored over time and space. These studies may include interventional study designs.<\/p>\n\n\n\nAction 2:<\/strong> By interacting with surveillance organizations in the human (Sant\u00e9 publique France), animal (ANSES) and environmental (AFB, INERIS) fields, we will set up methodological research to optimize the collection of surveillance data on antibiotic resistance and antibiotic consumption, as well as the collection and conservation of bacterial strains. The aim will be to better integrate data from the three sectors in order to characterize emergence and transmission pathways.<\/p>\n\n\n\nAction 3: <\/strong>Antibiotic resistance is a global issue, with the worldwide circulation of BMR and resistance genes via various genetic elements. We will encourage collaboration within international networks and analysis of the impact of international trade. Partnerships with low- and middle-income countries will be particularly encouraged.<\/p>\n\n\n\nAction 4:<\/strong> We will create a one-stop shop for biobanks of bacterial strains, particularly BMR, genetic supports and resistance vectors. We will develop \u201comics\u201d databases (complete bacterial genomes, resistome, metagenomic data from complex matrices – human or animal tissues or biological fluids, environmental matrices – transcriptomic and metabolomic data, etc.) from the three HAE ecosystems, which will be accessible for research purposes, taking into account all confidentiality constraints (in collaboration with axis 3<\/a>).<\/p>\n\n\n\n
Context<\/h3>\nAntibiotics are most often derivatives of natural compounds found in the environment, with their own metabolism. Antibiotic resistance is also a natural process that preceded their use by humans. The use of antibiotics, antiseptics and disinfectants on a bacterial species leads to the selection of resistant mutants that are able to multiply in the presence of these anti-infective agents. The phenomenon of selecting resistant variants to anti-infective agents following exposure exists in microbiology for all organisms, whether bacteria, viruses, fungi or parasites. The same is true of cytotoxic agents used in chemotherapy or insecticides used in vector control. Certain concepts of progressive selection of variants that escape treatment and their dissemination are common to these processes. However, the selection and transmission of bacterial resistance to antibiotics present two particularities that make their dynamics particularly complex. Firstly, these treatments will also affect human and animal microbiota, as well as microbial communities in the environment, by modifying their composition and selecting resistant strains which can then spread to other reservoirs. In addition, an important component of resistance results from the acquisition of resistance genes (ARGs) encoding efflux pumps or enzymes which, for example, inactivate an antibiotic, or modify its target. These resistance genes are frequently carried by plasmid or integrative mobile genetic elements (MGEs), which have the ability to pass from one bacterium to another within the same species, or between species that are even phylogenetically distant. The selection (emergence), transmission and dissemination of antibiotic resistance therefore involve not only the circulation of strains, but also that of EGMs in the multiple reservoirs constituted by human, animal and environmental populations under multiple evolutionary pressures.<\/p>\n<\/div><\/div>\n<\/div>\n\n\n\n
\nIssues<\/h3>\nAntibiotic resistance represents a major public health issue for both humans and animals. Surveillance networks<\/a> exist at multiple levels: national, with Sant\u00e9 publique France for human health, via the CNRs, ONERBA and the national missions of the CPIASs, and ANSES for animal health and the environment; international, with the WHO, OIE and ECDC in particular; but also at local level, at the level of a healthcare establishment. Antibiotic consumption by humans and animals and their release into the environment are also monitored. Alongside these surveillance activities, which are essential for identifying epidemiological changes in time and space, understanding the mechanisms of selection, transmission and dissemination of resistance requires a combination of approaches: i) an evolutionary approach to the selection dynamics of treatment-resistant strains capable of dissemination (and therefore of low biological cost), ii) a molecular approach to understand the mechanisms of acquisition and transfer of resistance genes and mutations, and iii) an ecological approach to understand and model the spatial interactions between microbiota and the intermittent selection pressures to which bacteria are subjected.<\/p>\n\n\n\nA key challenge for the future is to integrate innovative approaches into these studies to gain a detailed understanding of the processes involved (see also axis 3<\/a>): \u201comics\u201d approaches (genomics, metagenomics, transcriptomics, proteomics, and also metabolomics), \u201csingle cell\u201d or \u201csingle molecule\u201d studies, new imaging methods and mathematical and computational approaches, particularly learning approaches.<\/p>\n\n\n\nA second challenge will be to use mathematical tools to combine surveillance data and mechanistic knowledge to model the processes involved in the selection and dissemination of antibiotic-resistant strains and resistance genes in humans, animals and the environment. These models will make it possible to assess and predict the level of risk of acquisition and transmission of antibiotic resistance, associated with local or national antibiotic use policies, preventive healthcare measures, animal husbandry and water treatment procedures.<\/p>\n<\/div><\/div>\n<\/div>\n<\/div>\n\n\n\n
Research priorities<\/h3>\nSelection of resistance genes, resistant strains and resistance mechanisms<\/h4>\n\n\n\n
The emergence of a resistant clone is a complex process that combines four components that must be studied together:<\/p>\n\n\n\n
\n- Resistance genes and mechanisms: the first step in the selection of a new resistance mechanism is the capture of resistance genes in environmental reservoirs that are often little explored. Paradoxically, the environmental origin of major circulating resistance genes is still unknown. Once captured, resistance genes will have variable potential to evolve to target new antibiotics.<\/li>\n<\/ul>\n\n\n\n
\n- Chromosomal mutations: the selection of resistant strains also proceeds through the acquisition of mutations (SNPs, indels, recombination, amplification) in various systems directly or indirectly involved in the mode of action of an antibiotic or its accumulation in the bacterium.<\/li>\n<\/ul>\n\n\n\n
\n- The phenomena of persistence, tolerance and dormancy must be taken into account in the emergence and selection of resistant clones. These phenomena are under the control of genetic determinants that are still largely unknown, and are preliminary stages in the acquisition of mutations conferring resistance.<\/li>\n<\/ul>\n\n\n\n
\n- The selection and amplification of a resistant strain will depend on the selection pressure exerted by antibiotics and by numerous other molecules and\/or non-medicinal practices with a synergistic effect. This collateral selection pressure is often poorly understood, particularly for bacterial populations not directly targeted by treatment (species colonizing microbiota) or in the environment.<\/li>\n<\/ul>\n\n\n\n
Consequently, it is necessary not only to go beyond the catalog of these genes and mutations, but also to integrate the observations into a complex model to reconstruct the dynamics of the appearance of resistant clones and the underlying molecular mechanisms in terms of mutation selection, capture and transfer of resistance genes, and to identify the constraints involved in the success of a resistant clone, such as the compatibility of acquired resistance genes or EGMs with a genetic background, and in the successive acquisition of resistance genes, plasmids and mutations.<\/p>\n\n\n\n
Dissemination and transfer of clones and genes – reservoirs<\/h4>\n\n\n\n
Molecular epidemiology describes, for different species of pathogenic bacteria, the existence of dominant antibiotic-resistant clones and resistance genes associated with EGMs, as well as their distribution in different human, animal and environmental reservoirs. The population size of these clones can vary in time and space, on a local, national or international scale. The reasons for the \u201csuccess\u201d of these clones are still largely unknown, as are the reasons for their disappearance. Genomic sequencing and international cooperation should make it possible to identify these clones for major pathogenic species, as well as their circulation and geographical distribution in a \u201cOne Health\u201d dimension.<\/p>\n\n\n\n
The properties of these clones and the genetic determinants involved in their ability to disseminate and transmit between reservoirs are very diverse. They include the ability to colonize and persist in humans and animals or in the environment, resistance to stress, interactions with the host microbiota, and for EGMs carrying resistance genes, their capacity for intra- and inter-species transfer. The acquisition of resistance usually has a biological cost, and the ability to disseminate implies reducing this cost.<\/p>\n\n\n\n
Epidemic clones selected by these processes may have particular virulence properties (hyper- or hypo-virulence) which affect the risk associated with these clones and need to be better understood to be taken into account in diagnosis and surveillance. Resistant clones are intermittently subjected to selection pressure by antibiotics or antiseptics, often at low (sub-inhibitory) doses. They are also subject to host defenses (innate immunity, acquired immunity and vaccines) and environmental resilience. It is the result of these evolutionary and ecological constraints, and a clone’s ability to adapt, that determine the dynamics of resistant bacterial populations.<\/p>\n\n\n\n
<\/p>\n<\/div><\/div>\n\n\n\n
\nObjectives and action plan<\/h3>\n\n\n\nObjective 1 –<\/strong> To map the biodiversity of antibiotic resistance in the three Human-Animal-Environment (HAE) sectors and characterize the intra- and inter-sector transmission routes, as well as the bacterial and environmental factors involved in transmission.<\/h4>\nAction 1:<\/strong> We will set up hospital, community, animal health and environmental study sites (based in particular on existing workshop sites) enabling us to develop different research programs in environments monitored over time and space. These studies may include interventional study designs.<\/p>\n\n\n\nAction 2:<\/strong> By interacting with surveillance organizations in the human (Sant\u00e9 publique France), animal (ANSES) and environmental (AFB, INERIS) fields, we will set up methodological research to optimize the collection of surveillance data on antibiotic resistance and antibiotic consumption, as well as the collection and conservation of bacterial strains. The aim will be to better integrate data from the three sectors in order to characterize emergence and transmission pathways.<\/p>\n\n\n\nAction 3: <\/strong>Antibiotic resistance is a global issue, with the worldwide circulation of BMR and resistance genes via various genetic elements. We will encourage collaboration within international networks and analysis of the impact of international trade. Partnerships with low- and middle-income countries will be particularly encouraged.<\/p>\n\n\n\nAction 4:<\/strong> We will create a one-stop shop for biobanks of bacterial strains, particularly BMR, genetic supports and resistance vectors. We will develop \u201comics\u201d databases (complete bacterial genomes, resistome, metagenomic data from complex matrices – human or animal tissues or biological fluids, environmental matrices – transcriptomic and metabolomic data, etc.) from the three HAE ecosystems, which will be accessible for research purposes, taking into account all confidentiality constraints (in collaboration with axis 3<\/a>).<\/p>\n\n\n\n
Antibiotics are most often derivatives of natural compounds found in the environment, with their own metabolism. Antibiotic resistance is also a natural process that preceded their use by humans. The use of antibiotics, antiseptics and disinfectants on a bacterial species leads to the selection of resistant mutants that are able to multiply in the presence of these anti-infective agents. The phenomenon of selecting resistant variants to anti-infective agents following exposure exists in microbiology for all organisms, whether bacteria, viruses, fungi or parasites. The same is true of cytotoxic agents used in chemotherapy or insecticides used in vector control. Certain concepts of progressive selection of variants that escape treatment and their dissemination are common to these processes. However, the selection and transmission of bacterial resistance to antibiotics present two particularities that make their dynamics particularly complex. Firstly, these treatments will also affect human and animal microbiota, as well as microbial communities in the environment, by modifying their composition and selecting resistant strains which can then spread to other reservoirs. In addition, an important component of resistance results from the acquisition of resistance genes (ARGs) encoding efflux pumps or enzymes which, for example, inactivate an antibiotic, or modify its target. These resistance genes are frequently carried by plasmid or integrative mobile genetic elements (MGEs), which have the ability to pass from one bacterium to another within the same species, or between species that are even phylogenetically distant. The selection (emergence), transmission and dissemination of antibiotic resistance therefore involve not only the circulation of strains, but also that of EGMs in the multiple reservoirs constituted by human, animal and environmental populations under multiple evolutionary pressures.<\/p>\n<\/div><\/div>\n<\/div>\n\n\n\n
Issues<\/h3>\nAntibiotic resistance represents a major public health issue for both humans and animals. Surveillance networks<\/a> exist at multiple levels: national, with Sant\u00e9 publique France for human health, via the CNRs, ONERBA and the national missions of the CPIASs, and ANSES for animal health and the environment; international, with the WHO, OIE and ECDC in particular; but also at local level, at the level of a healthcare establishment. Antibiotic consumption by humans and animals and their release into the environment are also monitored. Alongside these surveillance activities, which are essential for identifying epidemiological changes in time and space, understanding the mechanisms of selection, transmission and dissemination of resistance requires a combination of approaches: i) an evolutionary approach to the selection dynamics of treatment-resistant strains capable of dissemination (and therefore of low biological cost), ii) a molecular approach to understand the mechanisms of acquisition and transfer of resistance genes and mutations, and iii) an ecological approach to understand and model the spatial interactions between microbiota and the intermittent selection pressures to which bacteria are subjected.<\/p>\n\n\n\nA key challenge for the future is to integrate innovative approaches into these studies to gain a detailed understanding of the processes involved (see also axis 3<\/a>): \u201comics\u201d approaches (genomics, metagenomics, transcriptomics, proteomics, and also metabolomics), \u201csingle cell\u201d or \u201csingle molecule\u201d studies, new imaging methods and mathematical and computational approaches, particularly learning approaches.<\/p>\n\n\n\nA second challenge will be to use mathematical tools to combine surveillance data and mechanistic knowledge to model the processes involved in the selection and dissemination of antibiotic-resistant strains and resistance genes in humans, animals and the environment. These models will make it possible to assess and predict the level of risk of acquisition and transmission of antibiotic resistance, associated with local or national antibiotic use policies, preventive healthcare measures, animal husbandry and water treatment procedures.<\/p>\n<\/div><\/div>\n<\/div>\n<\/div>\n\n\n\n
Research priorities<\/h3>\nSelection of resistance genes, resistant strains and resistance mechanisms<\/h4>\n\n\n\n
The emergence of a resistant clone is a complex process that combines four components that must be studied together:<\/p>\n\n\n\n
\n- Resistance genes and mechanisms: the first step in the selection of a new resistance mechanism is the capture of resistance genes in environmental reservoirs that are often little explored. Paradoxically, the environmental origin of major circulating resistance genes is still unknown. Once captured, resistance genes will have variable potential to evolve to target new antibiotics.<\/li>\n<\/ul>\n\n\n\n
\n- Chromosomal mutations: the selection of resistant strains also proceeds through the acquisition of mutations (SNPs, indels, recombination, amplification) in various systems directly or indirectly involved in the mode of action of an antibiotic or its accumulation in the bacterium.<\/li>\n<\/ul>\n\n\n\n
\n- The phenomena of persistence, tolerance and dormancy must be taken into account in the emergence and selection of resistant clones. These phenomena are under the control of genetic determinants that are still largely unknown, and are preliminary stages in the acquisition of mutations conferring resistance.<\/li>\n<\/ul>\n\n\n\n
\n- The selection and amplification of a resistant strain will depend on the selection pressure exerted by antibiotics and by numerous other molecules and\/or non-medicinal practices with a synergistic effect. This collateral selection pressure is often poorly understood, particularly for bacterial populations not directly targeted by treatment (species colonizing microbiota) or in the environment.<\/li>\n<\/ul>\n\n\n\n
Consequently, it is necessary not only to go beyond the catalog of these genes and mutations, but also to integrate the observations into a complex model to reconstruct the dynamics of the appearance of resistant clones and the underlying molecular mechanisms in terms of mutation selection, capture and transfer of resistance genes, and to identify the constraints involved in the success of a resistant clone, such as the compatibility of acquired resistance genes or EGMs with a genetic background, and in the successive acquisition of resistance genes, plasmids and mutations.<\/p>\n\n\n\n
Dissemination and transfer of clones and genes – reservoirs<\/h4>\n\n\n\n
Molecular epidemiology describes, for different species of pathogenic bacteria, the existence of dominant antibiotic-resistant clones and resistance genes associated with EGMs, as well as their distribution in different human, animal and environmental reservoirs. The population size of these clones can vary in time and space, on a local, national or international scale. The reasons for the \u201csuccess\u201d of these clones are still largely unknown, as are the reasons for their disappearance. Genomic sequencing and international cooperation should make it possible to identify these clones for major pathogenic species, as well as their circulation and geographical distribution in a \u201cOne Health\u201d dimension.<\/p>\n\n\n\n
The properties of these clones and the genetic determinants involved in their ability to disseminate and transmit between reservoirs are very diverse. They include the ability to colonize and persist in humans and animals or in the environment, resistance to stress, interactions with the host microbiota, and for EGMs carrying resistance genes, their capacity for intra- and inter-species transfer. The acquisition of resistance usually has a biological cost, and the ability to disseminate implies reducing this cost.<\/p>\n\n\n\n
Epidemic clones selected by these processes may have particular virulence properties (hyper- or hypo-virulence) which affect the risk associated with these clones and need to be better understood to be taken into account in diagnosis and surveillance. Resistant clones are intermittently subjected to selection pressure by antibiotics or antiseptics, often at low (sub-inhibitory) doses. They are also subject to host defenses (innate immunity, acquired immunity and vaccines) and environmental resilience. It is the result of these evolutionary and ecological constraints, and a clone’s ability to adapt, that determine the dynamics of resistant bacterial populations.<\/p>\n\n\n\n
<\/p>\n<\/div><\/div>\n\n\n\n
\nObjectives and action plan<\/h3>\n\n\n\nObjective 1 –<\/strong> To map the biodiversity of antibiotic resistance in the three Human-Animal-Environment (HAE) sectors and characterize the intra- and inter-sector transmission routes, as well as the bacterial and environmental factors involved in transmission.<\/h4>\nAction 1:<\/strong> We will set up hospital, community, animal health and environmental study sites (based in particular on existing workshop sites) enabling us to develop different research programs in environments monitored over time and space. These studies may include interventional study designs.<\/p>\n\n\n\nAction 2:<\/strong> By interacting with surveillance organizations in the human (Sant\u00e9 publique France), animal (ANSES) and environmental (AFB, INERIS) fields, we will set up methodological research to optimize the collection of surveillance data on antibiotic resistance and antibiotic consumption, as well as the collection and conservation of bacterial strains. The aim will be to better integrate data from the three sectors in order to characterize emergence and transmission pathways.<\/p>\n\n\n\nAction 3: <\/strong>Antibiotic resistance is a global issue, with the worldwide circulation of BMR and resistance genes via various genetic elements. We will encourage collaboration within international networks and analysis of the impact of international trade. Partnerships with low- and middle-income countries will be particularly encouraged.<\/p>\n\n\n\nAction 4:<\/strong> We will create a one-stop shop for biobanks of bacterial strains, particularly BMR, genetic supports and resistance vectors. We will develop \u201comics\u201d databases (complete bacterial genomes, resistome, metagenomic data from complex matrices – human or animal tissues or biological fluids, environmental matrices – transcriptomic and metabolomic data, etc.) from the three HAE ecosystems, which will be accessible for research purposes, taking into account all confidentiality constraints (in collaboration with axis 3<\/a>).<\/p>\n\n\n\n
Antibiotic resistance represents a major public health issue for both humans and animals. Surveillance networks<\/a> exist at multiple levels: national, with Sant\u00e9 publique France for human health, via the CNRs, ONERBA and the national missions of the CPIASs, and ANSES for animal health and the environment; international, with the WHO, OIE and ECDC in particular; but also at local level, at the level of a healthcare establishment. Antibiotic consumption by humans and animals and their release into the environment are also monitored. Alongside these surveillance activities, which are essential for identifying epidemiological changes in time and space, understanding the mechanisms of selection, transmission and dissemination of resistance requires a combination of approaches: i) an evolutionary approach to the selection dynamics of treatment-resistant strains capable of dissemination (and therefore of low biological cost), ii) a molecular approach to understand the mechanisms of acquisition and transfer of resistance genes and mutations, and iii) an ecological approach to understand and model the spatial interactions between microbiota and the intermittent selection pressures to which bacteria are subjected.<\/p>\n\n\n\n A key challenge for the future is to integrate innovative approaches into these studies to gain a detailed understanding of the processes involved (see also axis 3<\/a>): \u201comics\u201d approaches (genomics, metagenomics, transcriptomics, proteomics, and also metabolomics), \u201csingle cell\u201d or \u201csingle molecule\u201d studies, new imaging methods and mathematical and computational approaches, particularly learning approaches.<\/p>\n\n\n\n A second challenge will be to use mathematical tools to combine surveillance data and mechanistic knowledge to model the processes involved in the selection and dissemination of antibiotic-resistant strains and resistance genes in humans, animals and the environment. These models will make it possible to assess and predict the level of risk of acquisition and transmission of antibiotic resistance, associated with local or national antibiotic use policies, preventive healthcare measures, animal husbandry and water treatment procedures.<\/p>\n<\/div><\/div>\n<\/div>\n<\/div>\n\n\n\n The emergence of a resistant clone is a complex process that combines four components that must be studied together:<\/p>\n\n\n\n Consequently, it is necessary not only to go beyond the catalog of these genes and mutations, but also to integrate the observations into a complex model to reconstruct the dynamics of the appearance of resistant clones and the underlying molecular mechanisms in terms of mutation selection, capture and transfer of resistance genes, and to identify the constraints involved in the success of a resistant clone, such as the compatibility of acquired resistance genes or EGMs with a genetic background, and in the successive acquisition of resistance genes, plasmids and mutations.<\/p>\n\n\n\n Molecular epidemiology describes, for different species of pathogenic bacteria, the existence of dominant antibiotic-resistant clones and resistance genes associated with EGMs, as well as their distribution in different human, animal and environmental reservoirs. The population size of these clones can vary in time and space, on a local, national or international scale. The reasons for the \u201csuccess\u201d of these clones are still largely unknown, as are the reasons for their disappearance. Genomic sequencing and international cooperation should make it possible to identify these clones for major pathogenic species, as well as their circulation and geographical distribution in a \u201cOne Health\u201d dimension.<\/p>\n\n\n\n The properties of these clones and the genetic determinants involved in their ability to disseminate and transmit between reservoirs are very diverse. They include the ability to colonize and persist in humans and animals or in the environment, resistance to stress, interactions with the host microbiota, and for EGMs carrying resistance genes, their capacity for intra- and inter-species transfer. The acquisition of resistance usually has a biological cost, and the ability to disseminate implies reducing this cost.<\/p>\n\n\n\n Epidemic clones selected by these processes may have particular virulence properties (hyper- or hypo-virulence) which affect the risk associated with these clones and need to be better understood to be taken into account in diagnosis and surveillance. Resistant clones are intermittently subjected to selection pressure by antibiotics or antiseptics, often at low (sub-inhibitory) doses. They are also subject to host defenses (innate immunity, acquired immunity and vaccines) and environmental resilience. It is the result of these evolutionary and ecological constraints, and a clone’s ability to adapt, that determine the dynamics of resistant bacterial populations.<\/p>\n\n\n\n <\/p>\n<\/div><\/div>\n\n\n\n Action 1:<\/strong> We will set up hospital, community, animal health and environmental study sites (based in particular on existing workshop sites) enabling us to develop different research programs in environments monitored over time and space. These studies may include interventional study designs.<\/p>\n\n\n\n Action 2:<\/strong> By interacting with surveillance organizations in the human (Sant\u00e9 publique France), animal (ANSES) and environmental (AFB, INERIS) fields, we will set up methodological research to optimize the collection of surveillance data on antibiotic resistance and antibiotic consumption, as well as the collection and conservation of bacterial strains. The aim will be to better integrate data from the three sectors in order to characterize emergence and transmission pathways.<\/p>\n\n\n\n Action 3: <\/strong>Antibiotic resistance is a global issue, with the worldwide circulation of BMR and resistance genes via various genetic elements. We will encourage collaboration within international networks and analysis of the impact of international trade. Partnerships with low- and middle-income countries will be particularly encouraged.<\/p>\n\n\n\n Action 4:<\/strong> We will create a one-stop shop for biobanks of bacterial strains, particularly BMR, genetic supports and resistance vectors. We will develop \u201comics\u201d databases (complete bacterial genomes, resistome, metagenomic data from complex matrices – human or animal tissues or biological fluids, environmental matrices – transcriptomic and metabolomic data, etc.) from the three HAE ecosystems, which will be accessible for research purposes, taking into account all confidentiality constraints (in collaboration with axis 3<\/a>).<\/p>\n\n\n\nResearch priorities<\/h3>
Selection of resistance genes, resistant strains and resistance mechanisms<\/h4>\n\n\n\n
\n
\n
\n
\n
Dissemination and transfer of clones and genes – reservoirs<\/h4>\n\n\n\n
Objectives and action plan<\/h3>\n\n\n\n
Objective 1 –<\/strong> To map the biodiversity of antibiotic resistance in the three Human-Animal-Environment (HAE) sectors and characterize the intra- and inter-sector transmission routes, as well as the bacterial and environmental factors involved in transmission.<\/h4>