What innova*ve solu*ons to an*microbial resistance? Researches conducted at the Ins*tut Pasteur and in the Network

Transcription

1 What innova*ve solu*ons to an*microbial resistance? Researches conducted at the Ins*tut Pasteur and in the Network

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3 Two complementary approaches to address the AMR issue Policy to slow the development and spread of AMR Reduce consump*on in humans and in animals Use the right Ab combina*on Understanding the evolu*on, the dynamic and the ecology of an*bio*c resistance Smart surveillance in the hospital, the community, the farm Improving diagnos*c New an9bio9cs Iden*fica*on and characterisa*on of new targets Iden*fica*on and synthesis of ac*ve molecules Tes*ng promising candidates Vaccines and alterna*ve strategies

4 Objec*ves of AMR- IP To iden*fy research on an*bio*cs performed at IP- Paris and in the network To increase the visibility of the Ins*tut Pasteur and the IPIN as a major player in the field To coordinate the research on an*bio*cs by allowing a bejer awareness on what is done s*mula*ng collabora*ons helping to par*cipate to external calls Improve the ajrac*veness of the IP for the recruitment of scien*sts and group leaders in this field hjps://research.pasteur.fr/fr/program_project/figh*ng- an*bio*c- resistance/

5 Ac*vi*es of the group Mapping the research done on an*bio*cs Survey towards research units of the campus, the network and the plaporms Improving awareness on what is done Organiza*on of an internal scien*fic day (September 13) Invita*on of scien*sts from the IPIN Increase the visibility of the Ins*tut Pasteur IPIN mee*ng, par*cipa*on to the breakthrough session Organiza*on of an interna*onal conference (March 19-21, 2018) LabEx IBEID

6 45 Responses Epidemiology Global health (9) An*bio*c resistance genes, horizontal transfers (3) Resistance and mechanism of resistance (10) Target analysis (5) Drug screening - new an*bio*cs (9) "Natural" compounds (2) Alterna*ve to an*bio*cs (5) CITECH (2) Infec*on & Epidemiology (3) Structural Biology and chemistry (5) Genomes and Gene*cs (5) Cell Biology and Infec*on 6) Ins*tut Pasteur Network (9) Microbiology (13)

7 Knowing the enemy

8 Epidemiology, fields inves*ga*on and modelling Actors: Na*onal Reference Centres Units from the Interna*onal IP network Research units in epidemiology Outcome Biological samples (isolates, stool, serums) Data (epidemiology, socio- economical) Model of transmission, emergence, decline Global perspec*ve Human centred but new programs on animals and environmental samples

9 Isolates characteriza*on: popula*on genomics Strain typing based on genome sequencing Sequencing plaporm (PIBnet dedicated to public health programs) Bioinforma*cs: Strain typing (core genome MLST), resistome Databases Popula*on genomics Emergence of lineages (mul*- resistant, virulent) Rela*on between human and animal isolates Listeria, Klebsiella, Salmonella, Escherichia coli, Shigella, Staphylococcus aureus, Streptococcus agalac7ae, Neisseria meningi7dis

10 Mechanisms of resistance Genomic studies: Iden*fica*on of gene*c traits increasing resistance and allevia*ng the fitness cost Gene*c support of resistance and their mobility Host associa*on dissemina*on of clones and mobile gene*c elements Metagenome analysis geographic distribu*on Biochemical studies Cell wall Modelling of resistance Riboswitch Mechanis*c of resistance emergence (gene transfers and muta*ons) and dissemina*on (Integrons, ICE, plasmids, recombian*on)

11 Figh*ng the enemy

12 Target characterisa*on Structural analysis: o o o D- Ala:D- Lac ligase, VanA DNA gyrase β- lactamases Biochemical analysis o o o Secre*on systems for drug delivery Protein Protein interac*on as a target Top down proteomics The cell wall biosynthesis in different bacteria

13 Drug screening Screening plaporms CITECH PlaPorm (molecular interac*on, cellular, phenotype ) Chemistry Unit: enzyma*c ac*vity Ins*tut Pasteur in Seoul Screening Quorum sensing inhibi*on Kdo glycosyltransferases Apolipoprotein N- acyltransferase Nucleoside metabolism NAD(P) biosynthesis Divisome

14 Natural Compounds Bacteriocins: Listeriolysin S as an alterna*ve to an*bio*cs An*microbial pep*des The Pasteur cyanobacteria collec*on (PCC). Genome based iden*fica*on of biosynthe*c pathways of natural compounds

15 Alterna*ve to an*bio*cs Vaccines CRISPR- Cas9 Bacteriophages Elimina*ng biofilms and sensi*zing bacteria to an*bio*cs in biofilms Metals in associa*on with an*bio*cs (Bismuth against Helicobacter pylori) Targe*ng host bacteria interac*ons (epigene*cs)

16 Eligobiotics in action 1 1 An engineered phagemid attaches to the bacteria and injects a DNA circuit Cas9, tracrna and crrna are immediately synthesized and processed, starting to scan the bacterial genomes within minutes. If the target sequence is found in the bacterial genome, Cas9 will create a double strand-break that will lead to rapid cell death. When using the mutated version dcas9, the target sequence and can be silenced.

17 Alterna*ve to an*bio*cs Vaccines CRISPR- Cas9 Bacteriophages Elimina*ng biofilms and sensi*zing bacteria to an*bio*cs in biofilms Metals in associa*on with an*bio*cs (Bismuth against Helicobacter pylori) Targe*ng host bacteria interac*ons (epigene*cs)

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19 Alterna*ve to an*bio*cs Vaccines CRISPR- Cas9 Bacteriophages Elimina*ng biofilms and sensi*zing bacteria to an*bio*cs in biofilms Metals in associa*on with an*bio*cs (Bismuth against Helicobacter pylori) Targe*ng host bacteria interac*ons (epigene*cs)

20 Conclusion: research on AMR at the Ins*tut Pasteur From bed to molecules Broad range of exper*ses and diversity of point of view. Mostly research oriented Collabora*ons with clinicians Interest for applica*on of research and for collabora*ons with the industry.