Les projets scientifiques retenus par l’appel à projet « Antibiorésistance : Comprendre, Innover, Agir »

Les projets scientifiques retenus par l’appel à projet « Antibiorésistance : Comprendre, Innover, Agir »

Face au risque sanitaire majeur que représente la résistance aux antibiotiques et son augmentation à l’échelle mondiale, le gouvernement a mis en place en 2017 un groupe de travail pour préparer un programme prioritaire de recherche (https://ppr-antibioresistance.inserm.fr/fr/) sur l’antibiorésistance, suivant ainsi les recommandations du rapport Carlet « Tous ensemble sauvons les antibiotique » (juin 2015). Ce programme de 40 M€ a été annoncé par Mme Frédérique Vidal, Ministre de l’Enseignement Supérieur, de la Recherche et de l’Innovation (MESRI), le 14 novembre 2018 en clôture du colloque interministériel « Antibiorésistance : enjeux et besoins en recherche et innovation ». Dans le cadre de ce programme, un appel à projet (AAP) doté de 25 M€ a été lancé par l’ANR le 5 août 2020. Cet AAP couvrait l’ensemble des champs de la lutte contre l’antibiorésistance répartis en 4 challenges :

  • Dynamiques et contrôle de l’émergence, de la transmission et de la dissémination de l’antibiorésistance ;
  • Optimisation de l’usage des antibiotiques en médecines humaine et vétérinaire ;
  • Déterminants individuels, ethnologiques et sociologiques, économiques, politiques et culturels de l’antibiorésistance ;
  • Innovation thérapeutique.

Un Appel à Manifestation d’Intérêt (AMI) préalable a été lancé le 9 janvier 2020 pour favoriser les rapprochements de projets et l’attraction d’expertises complémentaires. Au total, 131 manifestations d’intérêt ont été déposées, témoignant de la richesse de la recherche française sur l’antibiorésistance. En réponse à l’AAP, 72 projets ont été soumis et évalués par un comité international qui a retenu 20 projets pour une audition en janvier 2021. Enfin, 11 projets répondant aux 4 challenges de l’AAP ont été retenus pour financement, dont vous trouverez une synthèse ci-dessous.

ANORUTI : Analyse de la non-réponse aux antibiotiques in vivo : application à l’infection urinaire à Escherichia coli

Coordinateur scientifique : Bruno Fantin
Institut porteur : Inserm
Institut partenaire : Institut Pasteur
Durée : 48 mois

En prenant comme exemple les infections urinaires, le projet ANORUTI se propose d’améliorer la compréhension des échecs de l’antibiothérapie in vivo et de fournir des solutions de diagnostic avec une meilleure précision de prédiction. L’objectif est de développer in vitro des plateformes expérimentales de bioréacteurs et un modèle pharmacocinétique/pharmacodynamique (PK/PD) à deux compartiments pour évaluer la croissance et les capacités de survie des bactéries dans différentes conditions expérimentales proches de l’infection urinaire. Des expériences in vivo seront réalisées chez la souris pour identifier l’ensemble des environnements in vitro à prendre en compte, et pour valider les prédictions faites in vitro.

DREAM : Dynamique de le RÉsistance aux Antibiotiques dans le Microbiote intestinal humain: combinaison d’une cohorte informée sur la nutrition à des études quantitatives sur un modèle in vitro d’intestin

Coordinateur scientifique : Olivier Tenaillon
Institut porteur : Inserm
Instituts partenaires : Université Sorbonne Paris Nord ; CEA/Institut de biologie François-Jacob/Genoscope
Durée : 72 mois

Le microbiote intestinal peut être impacté lors d’un traitement antibiotique et constitue ainsi un environnement essentiel pour l’émergence et la propagation de l’antibiorésistance. Étonnamment, la réponse à un traitement en termes de sélection des gènes de résistance est très variable d’un individu à l’autre. L’hypothèse que le microbiote lui-même pourrait moduler l’impact du traitement et expliquer cette diversité de réponse reste très peu explorée. Ainsi, nous avons constitué un consortium multidisciplinaire afin d’analyser précisément la dynamique de génération et sélection de l’antibiorésistance dans un modèle de microbiote intestinal in vitro combiné à l’étude d’une cohorte finement caractérisée en termes d’alimentation, Nutrinet-Santé.

DYASPEO : Dynamique de la propagation, de la persistance et de l’évolution de l’AMR entre les humains, les animaux et leur environnement

Coordinateur scientifique : Jean-Yves Madec
Institut porteur : Anses
Instituts partenaires : Ecole Nationale Vétérinaire d’Alfort ; Assistance Publique-Hôpitaux de Paris, Inserm ; Institut Pasteur ; Centre Hospitalier Universitaire de Clermont-Ferrand ; CNRS
Durée : 72 mois

Les stratégies de contrôle de la transmission de l’antibiorésistance de l’animal à l’Homme sont aujourd’hui principalement centrées sur la chaîne alimentaire. Pour autant, c’est le Staphylococcus aureus résistant à la méticilline (SARM) transmis à l’Homme par contact avec le porc – et non par l’alimentation – qui a entraîné la seule crise politique majeure en Europe depuis 20 ans. DYASPEO fait l’hypothèse que le contact avec un animal de compagnie (un foyer sur deux en France) joue également un rôle, et associe des compétences en médecine humaine, vétérinaire, sciences sociales, génomique, mathématiques, modélisations in vitro/in vivo, pour clarifier cette question.

MicroFlu4AMR : Caractérisation et criblage par haut débit des communautés bactériennes dans le sol : mécanismes de la résistance aux antibiotiques et découverte de nouveaux antibiotique

Coordinateur scientifique : Andrew Griffiths
Institut porteur : École supérieure de physique et chimie industrielle de Paris (ESPCI Paris)
Instituts partenaires : Université Bourgogne Franche-Comté ; INRAE ; DEINOVE SA
Durée : 48 mois

Le sol est un formidable réservoir de biodiversité microbienne et les antibiotiques existants sont principalement des métabolites secondaires produits par ces microorganismes. L’évolution et la dissémination des antibiotiques et des résistances aux antibiotiques sont intimement liées. Cette diversité fonctionnelle sera caractérisée à l’aide i) d’approches métagénomiques et ii) de criblages phénotypiques et génotypiques à très haut débit en micro-fluidique en gouttes. Un système d’évolution en laboratoire servira à l’étude des mécanismes de contrôle, d’émergence et de dissémination des gènes. Cela donnera un aperçu sans précédent de la diversité et des interactions entre les antibiotiques et les mécanismes de synthèse et de résistance aux antibiotiques, et permettra potentiellement la découverte de nouveaux antibiotiques et mécanismes de résistance.

Mustart : Stratégies multiparamétriques contre la résistance aux antibiotiques de la tuberculose

Coordinateur scientifique : Alain Baulard
Institut porteur : Institut Pasteur de Lille
Instituts partenaires : Inserm ; CNRS Délégation Occitanie Ouest ; Sorbonne Université ; Institut Pasteur ; Institut national des sciences appliquées (INSA) de Toulouse ; CEA ; Hospices civils de Lyon
Durée : 48 mois

La lutte contre la tuberculose multi-résistante requiert des traitements plus courts et des biomarqueurs d’efficacité du traitement en temps réel. Fruits de l’expérience des 9 partenaires de Mustart, des molécules antituberculeuses innovantes seront assemblées pour stimuler les défenses de l’hôte, réduire la virulence du bacille, détruire ses formes dormantes et persistantes, fonctionner en synergie, et ainsi réduire le temps de traitement et les risques d’échappement. Le deuxième objectif de Mustart est d’identifier à l’aide de techniques innovantes de spectrométrie de masse et de RMN des biomarqueurs de l’évolution du traitement des patients afin d’éviter les échecs thérapeutiques et l’émergence de bacilles résistants.

NAILR : Nouveaux anti-infectieux à résistance limitée

Coordinateur scientifique : Vincent Cattoir
Institut porteur : Université de Rennes 1
Instituts partenaires : Inserm – Délégations régionale Paris 07 et Auvergne Rhône Alpes, Institut Pasteur, Sorbonne Université, Anses
Durée : 60 mois

L’objectif du projet est de caractériser en profondeur une nouvelle famille de peptidomimétiques anti-infectieux (appelés heptapseudopeptides) dérivés d’une toxine bactérienne. Le consortium réunit 7 partenaires aux compétences complémentaires dans des disciplines variées : microbiologistes cliniques et moléculaires, biochimistes, structuralistes, vétérinaires, cliniciens, pharmacologues, écologistes et experts du microbiote intestinal. Organisé en 6 tâches, le projet vise à définir les principales propriétés de ces nouveaux composés : activité in vitro, mécanisme(s) d’action, cibles moléculaires et mécanismes de résistance, paramètres PK/PD et efficacité in vivo sur différents modèles animaux d’infection. Enfin, l’impact de ces peptides sur le microbiote intestinal humain sera étudié, ainsi que leur stabilité dans l’environnement (eau, sol, sédiments) et leur impact sur les communautés microbiennes environnementales.

NASPEC : Antibiotiques à spectre étroit pour lutter contre l’émergence de la résistance bactérienne

Coordinateur scientifique : Michel Arthur
Institut porteur : Université de Paris
Instituts partenaires : CNRS – Délégations régionales Île-de-France Gif-sur-Yvette, Alpes et Paris-Centre ; Institut Pasteur.
Durée : 60 mois

L’objectif est de développer de nouveaux antibiotiques sélectivement actifs sur les pathogènes critiques définis par l’OMS en combinant au sein d’une prodrogue deux β-lactamines. L’hydrolyse du premier noyau β-lactame libèrera la seconde β-lactamine sous une forme active exclusivement dans le périplasme des bactéries productrices de carbapénémases ou de céphalosporinases. Une approche combinatoire sera développée qui reposera sur la diversité chimique des β-lactamines. Cette approche permettra de réduire la pression de sélection liée à l’utilisation d’antibiotiques à large spectre limitant ainsi les dommages collatéraux sur les flores commensales en termes de sélection de résistances, de dysbiose et d’immunostimulation.

OrA-NEAT : Développement et évaluation d’un programme personnalisé de bon usage des antibiotiques adapté aux besoins des EHPAD français

Coordinatrice scientifique : Nelly Agrinier
Institut porteur : Université de Lorraine
Instituts partenaires : Fondation nationale des sciences politiques (FNSP) ; Université de Bordeaux : CHU de Nantes
Durée : 72 mois

Les programmes de bon usage des antibiotiques (BUA) ont prouvé leur efficacité dans les hôpitaux et les maisons de retraite principalement nord-américaines. La transférabilité de ces résultats aux établissements d’hébergement pour personnes âgées dépendantes (EHPAD) français reste à explorer. Pour ce faire, le projet OrA-NEAT vise à : (i) comprendre les comportements et attitudes des professionnels de santé conduisant à un usage inapproprié des antibiotiques en EHPAD ; (ii) développer un programme de BUA multi-composantes, adaptable au contexte de chaque EHPAD ; (iii) évaluer l’efficacité, la pérennité, la mise en place et la transférabilité d’un tel programme dans l’ensemble des EHPAD français.

PHAG-ONE : Développement, production et utilisation en clinique de phages thérapeutiques pour traiter les infections dues aux bactéries résistantes aux antibiotiques

Coordinateur scientifique : Frédéric Laurent
Institut porteur : Hospices civils de Lyon
Instituts partenaires : Inserm ; CNRS ; CEA ; Université Claude-Bernard Lyon 1 ; Université de Versailles Saint-Quentin-en-Yvelines ; Université de Bordeaux
Durée : 72 mois

Le projet PHAG-ONE a pour objectifs d’isoler, caractériser, produire et fournir des phages thérapeutiques académiques à coût maîtrisé qui seront utilisés en clinique. Trois espèces bactériennes cibles ont été sélectionnées : Staphylococcus aureus, Staphylococcus epidermidis et Escherichia coli. Des études d’efficacité et PK/PD in vitro et in vivo, la mise en place de cohortes d’utilisation compassionnelles et d’un essai clinique ainsi que le développement d’outils innovants d’imagerie pour le titrage des phages et pour la réalisation de phagogrammes standardisés automatisés et rapides font aussi partie des objectifs. De façon concomitante, une analyse socio-anthropologique de la production de connaissance entourant l’émergence de cette innovation biomédicale ainsi que celle de son environnement règlementaire et institutionnel sera conduite.

Seq2Diag : Séquençage du génome entier et intelligence artificielle pour caractériser et diagnostiquer la résistance aux antibiotiques et la capacité d’échapper au traitement.

Coordinateur scientifique : Philippe Glaser
Institut porteur : Institut Pasteur
Instituts partenaires : Université Paris-Saclay, Laboratoire Interdisciplinaire des Sciences du Numérique ; Inserm – Délégations régionales Nouvelle Aquitaine et Paris 11 ; CNRS – Délégation Île-de-France Gif-sur-Yvette, Anses, Université de Franche-Comté
Durée : 60 mois

Le séquençage génomique a révolutionné la surveillance microbiologique et l’épidémiologie moléculaire. L’objectif du projet Seq2Diag est de faire une preuve de concept de son utilisation dans les laboratoires hospitaliers et vétérinaires comme outil de diagnostic pour un test in silico de sensibilité aux antibiotiques. Ce projet multidisciplinaire associe des compétences en microbiologie clinique humaine et animale, en génomique, en pharmacologie, en microbiologie moléculaire et en machine learning. Ces analyses, basées sur une grande diversité de souches cliniques d’Escherichia coli, de Klebsiella pneumoniae et de Pseudomonas aeruginosa, permettront également de découvrir de nouveaux mécanismes de résistance et d’échappement au traitement.

TheraEPI : Une thérapie fondée sur l’épigénétique pour contourner la résistance

Coordinatrice scientifique : Paola B. Arimondo
Institut porteur : Institut Pasteur
Instituts partenaires : INRAE ; Université de Paris – Epigénétique et destin cellulaire
Durée : 60 mois

Tous les organismes ont des défenses, codées par leur génome, pour empêcher les microbes de proliférer. Les microbes y échappent en modifiant l’« épigénome» de leur hôte pour reprogrammer sa lecture. TheraEPI propose de contrecarrer les modifications épigénétiques induites par les microbes, pour rétablir les capacités de défense de l’hôte. Le consortium rassemble des équipes de chimistes et de biologistes pour identifier des molécules actives au niveau épigénétique dans sept modèles d’infection, y compris par des souches antibio-résistantes. L’optimisation des molécules actives, l’identification de leurs cibles et des essais en modèles infectieux complexes aboutiront à des nouvelles molécules candidates pour développer des nouveaux antibiotiques.

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