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

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

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

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

16. Spain Egypt Morocco Iraq Switzerland The epidemic of NDM-1 producers

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