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
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4. Bacterial SOS response Mutations of resistance Mobilization of mobile elements Expression of resistance genes Stressful conditions including Antibiotics
5. Gene dissemination accounts for 80% of clinical resistances Food Horizontal Gene Transfer CONTACT ENVIRONMENT Water, Soils, … ANIMAL HUMAN
6. Gene dissemination relies on diverse genetic vehicles integron tranposon plasmids ATB Induce the SOS response Gene transfer Induces the SOS response
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. 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
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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. 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. 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
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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. 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
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. 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
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Editor's Notes
- Objectifs de recherche (en « bullet points ») - Technologies et/ou ressources utilisées pour y parvenir (en « bullet points »)
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