En moins d’un siècle, l’utilisation des antibiotiques a conduit à la sélection, à l’émergence et à la propagation de souches bactériennes résistantes. Qualifiée de pandémie silencieuse par l’OMS, la résistance aux antimicrobiens est considérée comme l’une des plus grandes menaces pour l’humanité, en raison de son impact majeur en termes de morbidité et de mortalité, et pourrait être la première cause de décès dans le monde d’ici 2050. Il est désormais urgent de trouver des méthodes alternatives aux antibiotiques pour combattre les infections bactériennes dans le cadre d’une approche “Une seule santé” afin de protéger l’environnement et de réduire la charge et le coût des soins de santé en médecine humaine et vétérinaire. Parallèlement à l’utilisation correcte des antimicrobiens, et sur la base de nouvelles stratégies, plusieurs leviers sont envisagés pour limiter l’émergence et la propagation de la résistance, et pour combattre et prévenir les infections bactériennes. Forte d’une large expertise en microbiologie et alimentée par des fonds internes, l’unité Micalis s’est fixé un axe transversal regroupant ses forces dans ce domaine pour contribuer à réduire l’utilisation des antibiotiques et à prévenir les infections chez l’homme et l’animal.
Biofilms, diffusion-reaction, tolerance/resistance, resensitisation, cross-resistance
Our team is working on the pathophysiology of Clostridioides difficile. Our research activities related to the FAMe axis are focused on
Keywords : bacterial surface, biofilm, vaccine, probiotics
PIA Project iCFRee funded by France 2023 for the production and novel antimicrobial peptides and proteins in cell-free systems.
ANR DREAMY project builds mathematical models (deterministic and stochastic) of bacteriophage secretion and infection, for future applications in phage therapy and microbiota engineering.
Synthetic Biology
Peptides, including ribosomally-synthesized and post-translationally modified peptides (RiPPs), are promising candidates to develop innovative antibiotics. Indeed, they are generally regarded as specific in order to preserve the human microbiota, safe and to minimally trigger the development of resistance mechanisms.
In the ChemSyBio team, we are interested in the discovery of novel RiPPs and the biochemical and structural study of the enzymes involved in RiPP biosynthesis. Our team has identified and characterized novel RiPPs and deciphered their biosynthetic pathway. Notably, we have found key enzymes, radical SAM enzymes, involved in the installation of unprecedented post-translational modifications that confer their bioactivity to numerous RiPPs.
Recent work from our lab has shown that RiPPs and radical SAM enzymes are present in large numbers in the bacteria that colonize humans and make up the human microbiota. Although these bacteria and their genes represent a considerable genetic potential, known as the microbiome, our knowledge is still limited and one main goal of our team is to mime the human microbiome for novel antibiotics.
Keywords: RiPP (ribosomally synthesized and post-translationally modified peptides), peptides, antibiotics, enzyme catalysis, microbiome, natural products, structural biology
Enterococcus faecalis and Enterococcus faecium, rank among the top five causes of opportunistic infections in humans and Enterococcus cecorum has become a major cause of lameness in poultry. Our research on the molecular, cellular and physiological mechanisms of pathogenesis has led us to investigate novel non-antibiotic preventive or therapeutic strategies against enterococci. We have identified a consortium of commensal bacteria that improves the restoration of the gut microbiota after antibiotic-induced dysbiosis and the barrier effect against vancomycin-resistant enterococci (VRE) in mice. We determined tentative cutoffs for around twenty antimicrobials on a large collection of E. cecorum and isolated virulent bacteriophages in order to develop phage solutions directed against E. cecorum.
Enterococcal genetics, , ecological and cellular microbiology, anaerobic microbiology, phage biology.
Laurentie et al. J Clin Microbiol 2023; DOI: 10.1128/jcm.01445-22.
Keywords : Enterococcus, pathobiont, gut colonization resistance, phages
The Epimic team studies the molecular basis of persistent bacterial infections by using as a model the facultative intracellular pathogen L. monocytogenes. We have shown that during long-term infection in epithelial cells, Listeria enters a slow-replicating/ quiescent state which is associated with antibiotic tolerance. We are interested in the characterization of the signaling events and the molecular players that regulate the transition between the replicative and dormant state.
Cell biology and microscopy
Molecular biology and microbiology
PMID: 29190284, 34858876
https://doi.org/10.1101/2023.11.16.566987
Insect in vivo infection model : Galleria mellonella used to:
Development of quorum-quenching molecules targeting virulence regulators.
The role of biofilm structure/composition in the protection against Clostridioides difficile growth +/- antibiotics
Keywords. Insect infection model, Bacillus cereus, quorum sensing inhibition, Clostridioides difficile, biofilm
Staphylococcus aureus is a member of ESKAPE group from World Health Organization. Treatment of S. aureus infections is hampered by the organism’s ability to resist many antibiotics. In the team, we are developing researches into resistance mechanisms: role of exogenous fatty acids, role of phages, role of mutations leading to multi-resistant variants. We are also developing biocaptors for detecting S. aureus in complex environments (food, blood).
Keywords : S. aureus, adaptation, antibiotic resistance, biocaptor, mechanisms.
We are exploring peptidoglycan structural modifications in various pathogenic Gram-positive bacteria in the frame of collaborations (ANR-funded or intra-Micalis) to decipher the molecular basis of
Keywords : cell wall, peptidoglycan, Gram-positive bacteria, persistence
For bacterial pathogens exhibiting ever increasing levels of resistance to antibiotics, phages are becoming a serious alternative for treatment. The team isolated and characterized virulent phages against clinical isolates of Enterococcus faecalis, and more recently against E. faecium, a pathogen listed by the WHO for which new antibiotics are urgently needed. We also have expertise in evolution experiments to enlarge phage host range, as most natural phages infect only few strains within a given species. As virulent phages are not available for all pathogens, a new approach consists in using temperate phages and derive mutants that only perform lytic cycles. The team’s long-standing expertise in temperate phages of Escherichia coli has led us to characterize atypical lytic induction cycles, in order to broaden our knowledge of the lysis/lysogeny control in temperate phages, and thus optimize the chances of success in creating efficient “lytic” mutants.
Keywords: phage-bacteria interactions; phage host range expansion; phage evolution; phage therapy; lysis-lysogeny
The PhylHom team focuses on interactions between the human microbiome and xenobiotic exposures ranging from diet to drug therapies and subsequent impact on microbial communities and human health across different stages of life. Current research activities related to antibioresistance include characterization of antimicrobial resistance elements microbiome from clinical cohorts and engineered systems. The team works on various antimicrobial resistance mechanisms induced by host-targeted drugs within the gut microbiome communities. The team also aims to develop nutritional strategies to modulate microbial metabolites to reduce abundance of antimicrobial resistance genes in the human gut.
Keywords: Pharmaceuticals, resistome, gene transfer, microbial communities, exposome
The PIMs (Pathogens, Immunity and Microbiota) team is expert in the study of bacterial resistance to the host immune system. We characterize on one hand, the effects of the immune response on pathogenic bacteria in a pathobiome context, and on the other hand we develop new strategies to combat bacterial infections, mainly of the ESKAPE group (ie, K. pneumoniae, P. aeruginisa, E. coli) for which the WHO has recently pointed an alarming antibio-resistance issue. Promising drug candidates are currently tested for safety to the host and for activity against serious threat pathogens.
Finally, we develop communication means to increase reach out and large public awareness.
Our team is leader in the identification of probiotic and commensal bacteria with potential beneficial effects on the host, including antimicrobial effects. Our team is also at the forefront of the development of genetically modified bacteria able to produce and deliver therapeutic molecules, including antimicrobial peptides (AMPs). This application paves the way for the use of these microorganisms (known as Next-Generation Probiotics or NGPs) for the controlled production of the AMP of interest in situ. This strategy would solve: i) the replacement of the excessive use of antibiotics, ii) the problem of the cost of AMPs production and iii) the delivery to the site of infection.
