2.3 marie-cécile ploy

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  • - Objectifs de recherche (en « bullet points ») - Technologies et/ou ressources utilisées pour y parvenir (en « bullet points »)
  • 2.3 marie-cécile ploy

    1. 1. Resistance to Antibiotics Emerging threats and New molecular targets Marie-Cécile Ploy Avenir Inserm Limoges University, France Patrice Nordmann U 914 Inserm South-Paris Medical School, K-Bicêtre, France
    2. 2. <ul><li>Worldwide public health issue </li></ul><ul><li>All antibiotic families are concerned </li></ul><ul><li>Infections difficult to treat </li></ul>Antibiotic resistance
    3. 3. Improve knowledge on antibiotic resistance acquisition Genetics, dissemination, detection New therapeutic strategies to fight the resistance Fighting the resistance <ul><li>Good practices in antibiotic prescription </li></ul><ul><li>Hygiene procedures </li></ul>
    4. 4. Bacterial SOS response Mutations of resistance Mobilization of mobile elements Expression of resistance genes Stressful conditions including Antibiotics
    5. 5. Gene dissemination accounts for 80% of clinical resistances Food Horizontal Gene Transfer CONTACT ENVIRONMENT Water, Soils, … ANIMAL HUMAN
    6. 6. Gene dissemination relies on diverse genetic vehicles  integron  tranposon plasmids  ATB Induce the SOS response Gene transfer Induces the SOS response 
    7. 7. Specific role of Integrons in antibiotic resistance Science 2009, Mobile DNA 2011 Stress / SOS response Cassette intI Pc attI Pc intI attC1 attC1 Antibiotics Pint -35 -10 Site LexA intI LexA ssDNA- RecA IntI LexA Pint -35 -10 Site LexA intI
    8. 8. From resistance to susceptibility: search for inhibitors SOS system Pint attI -35 -10 intI ATB stress LexA Binding site IntI1 active protein Inhibition of integrase Global effect on IntI1 expression and horizontal gene transfer Inhibition of gene cassettes acquisition ssDNA- RecA LexA Pint attI -35 -10 LexA intI Inhibition of SOS response
    9. 9. Perspectives <ul><li>Importance of SOS response in antibiotic resistance </li></ul><ul><li>Antibiotic-induced mechanism </li></ul><ul><li>Find molecules co-administrated with antibiotics </li></ul><ul><li>to prevent resistance </li></ul><ul><li>Which targets ? </li></ul><ul><ul><li>Integrase of integrons ? Regulators of SOS system ? </li></ul></ul><ul><ul><li>Next steps </li></ul></ul><ul><ul><li>High-throughput screening, animal models </li></ul></ul>
    10. 10. Hospital Multidrug resistance : a major public health issue; 2011 update Methicillin-resistant Staph Vancomycin-resistant enterococci P. aeruginosa Multidrug resistance Enterobacteriaceae Carbapenemase Community Enterobacteriaceae Extended-spectrum β-lactamases A. baumannii pandrug resistance
    11. 11. Hospital Multidrug resistance : a major public health issue; 2011 update Methicillin-resistant Staph Vancomycin-resistant enterococci P. aeruginosa Multidrug resistance Enterobacteriaceae Carbapenemase Community NDM-1 superbugs Enterobacteriaceae Extended-spectrum β-lactamases A. baumannii pandrug resistance
    12. 12. 2010: spread of NDM-1 producers in Gram-negatives ( Enterobacteriaceae, Acinetobacter baumannii …) from India/Pakistan/Bangladesh to the UK bla NDM-1 -positive bacterial clones, and isolates Plasmids Kumarasamy et al., Lancet Infect. Dis. 2010, 10:597
    13. 13. Poirel L, Ros L, Carricajo A, Berthelot P, Pozetto B, Bernabeu S,,Nordmann P Extremely drug-resistant C. freundii in a patient returning from India and producing NDM-1 and other Carbapenemases. Antimicrob. Agents Chemother, 2011; 55,447-8 From multidrug resistance to pandrug resistance !! <ul><ul><li>Bacterial species </li></ul></ul><ul><ul><li>Escherichia coli, K. pneumoniae </li></ul></ul><ul><ul><li>and other Enterobacteriaceae </li></ul></ul><ul><ul><li>A. baumannii, P. aeruginosa </li></ul></ul><ul><ul><li>Infections </li></ul></ul><ul><li>Urinary tract infections </li></ul><ul><li>Device-associated infections </li></ul><ul><li>Pneumonia, peritonitis… </li></ul><ul><li>Hospital and community- </li></ul><ul><li>acquired infections </li></ul>
    14. 14. The genetics of bla NDM-1 IS EC33 bla NDM-1 IS Sen4 Δ Ph.ribosyl anthranilate isomerase Escherichia coli bleomycin resistance protein ΔIS Aba125
    15. 15. The genetics of bla NDM-1 :from A. baumannii to E. coli IS EC33 bla NDM-1 IS Sen4 Δ Ph.ribosyl anthranilate isomerase Escherichia coli bleomycin resistance protein ΔIS Aba125 bla NDM-1 IS Aba125 bleomycin resistance protein A. baumannii IS Aba125
    16. 16. Spain Egypt Morocco Iraq Switzerland The epidemic of NDM-1 producers
    17. 17. Spain Egypt Morocco Iraq Switzerland The epidemic of NDM-1 producers Identification 10 hotspots of NDM-1 producers; the usefulness of an international network (labs, n= 36)
    18. 18. Susceptibility testing (Automated systems, disk diffusion, ) Molecular identification of carbapenemase genes ESBL screening medium Screening of carrriers (stools) How to detect NDM-1 producers ? Nordmann et al. , J. Clin Microbiol. 2011. Infection Carriage
    19. 19. <ul><ul><li>Discover novel resistance determinants and their epidemiology </li></ul></ul><ul><ul><ul><li>- emergence worldwide in clinically-significant bacteria, mostly in Gram- negative </li></ul></ul></ul><ul><ul><ul><li>- Enterobacteriaceae Pseudomonas aeruginosa and Acinetobacter baumannii (resistance to ß-lactams, fluoroquinolones, aminoglycosides…..) </li></ul></ul></ul><ul><ul><li>Understand genetics and biochemistry of antibiotic resistance </li></ul></ul><ul><ul><li>determinants </li></ul></ul><ul><ul><li>Develop novel diagnostic tools </li></ul></ul><ul><ul><li>Evaluate and develop novel antibiotic molecules </li></ul></ul><ul><ul><li>ISI Web of Knowledge- Microbiology, 2011, P.Nordmann; 24 th /2682, #1 in France </li></ul></ul>Perspectives
    20. 20. Conflits d’intérêt <ul><li>MC Ploy </li></ul><ul><ul><li>bioMérieux, Sanofi Pasteur, GSK, Pfizer </li></ul></ul><ul><li>P Nordmann </li></ul><ul><ul><li>bioMérieux, Becton Dickinson, Septeos, Sanofi Aventis, GSK, Pfizer </li></ul></ul>

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