2.3 marie-cécile ploy
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Transcript of 2.3 marie-cécile ploy
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Resistance to AntibioticsEmerging threats and New molecular
targetsMarie-Cécile Ploy
Avenir InsermLimoges University, France
Patrice NordmannU 914 Inserm
South-Paris Medical School, K-Bicêtre, France
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• Worldwide public health issue
• All antibiotic families are concerned
• Infections difficult to treat
Antibiotic resistance
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• Good practices in antibiotic prescription
• Hygiene procedures
Improve knowledge on antibiotic resistance acquisition
Genetics, dissemination, detection
New therapeutic strategies to fight the resistance
Fighting the resistance
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Bacterial SOS response
Mutations of resistance
Mobilization of mobile elements
Expression of resistance genes
Stressful conditionsincluding
Antibiotics
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Gene dissemination accounts for 80% of clinical resistances
CONTACT
ENVIRONMENTWater, Soils, …
ANIMAL HUMAN
Food
Horizontal Gene
Transfer
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Gene dissemination relies on diverse genetic vehicles
integrontranposon
plasmids
ATB
Induce the SOS response
Gene transfer
Induces the SOS response
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Specific role of Integrons in antibiotic resistance
Cassette
intIPc
attI
PcintI attC1 attC1
Science 2009, Mobile DNA 2011
Antibiotics
Stress /
SOS responsePint
-35 -10
SiteLexA
intILexA
ssDNA-RecA
IntI
LexA
Pint
-35 -10
SiteLexA
intI
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From resistance to susceptibility: search for inhibitors
SOS system
IntI1active
protein
Inhibition of integrase
Global effect on
IntI1 expression
and horizontalgene transfer
Inhibition of gene cassettes acquisition
Pint
attI-35-10intI
ssDNA-RecA
LexA
Pint
attI
-35-10
LexA
intIATB stress
Inhibition of SOS response
LexABinding site
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Perspectives
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Importance of SOS response in antibiotic resistanceAntibiotic-induced mechanism
Find molecules co-administrated with antibiotics to prevent resistance
Which targets ?Integrase of integrons ? Regulators of SOS system ?
Next steps High-throughput screening, animal models
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Hospital
Multidrug resistance : a major public health issue; 2011 update
Methicillin-resistant Staph
Vancomycin-resistant enterococci
P. aeruginosa Multidrug resistance
Enterobacteriaceae Extended-spectrum β-lactamases
Enterobacteriaceae Carbapenemase
A. baumannii pandrug resistance
Community
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Hospital
Multidrug resistance : a major public health issue; 2011 update
Methicillin-resistant Staph
Vancomycin-resistant enterococci
P. aeruginosa Multidrug resistance
Enterobacteriaceae Extended-spectrum β-lactamases
Enterobacteriaceae Carbapenemase
A. baumannii pandrug resistance
Community
NDM-1 superbugs
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2010: spread of NDM-1 producers in Gram-negatives
(Enterobacteriaceae, Acinetobacter baumannii…)
from India/Pakistan/Bangladesh to the UK
blaNDM-1-positive bacterial clones, and isolates
Plasmids
Kumarasamy et al., Lancet Infect. Dis. 2010, 10:597
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Poirel L, Ros L, Carricajo A, Berthelot P, Pozetto B, Bernabeu S,,Nordmann PExtremely drug-resistant C. freundii in a patient returning from India and producing NDM-1 and otherCarbapenemases. Antimicrob. Agents Chemother, 2011; 55,447-8
From multidrug resistance to pandrug resistance !!
Bacterial species
Escherichia coli, K. pneumoniae
and other Enterobacteriaceae
A. baumannii, P. aeruginosa
Infections
Urinary tract infections Device-associated infections Pneumonia, peritonitis…
Hospital and community- acquired infections
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The genetics of blaNDM-1
ISEC33blaNDM-1 ISSen4
ΔPh.ribosylanthranilateisomerase
Escherichia coli
bleomycin resistance protein
ΔISAba125
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The genetics of blaNDM-1 :from A. baumannii to E. coli
ISEC33blaNDM-1 ISSen4
ΔPh.ribosylanthranilateisomerase
Escherichia coli
bleomycin resistance protein
ΔISAba125
blaNDM-1ISAba125 bleomycin resistance protein A. baumannii
ISAba125
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Spain
EgyptMorocco
Iraq
Switzerland
The epidemic of NDM-1 producers
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Spain
EgyptMorocco
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The epidemic of NDM-1 producers
Identification
10 hotspots of NDM-1 producers; the usefulness of an
international network (labs, n=
36)
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Susceptibility testing
(Automated systems, disk
diffusion, )
Molecular identification of carbapenemase genes
ESBL screening medium
Screeningof carrriers (stools)
How to detect NDM-1 producers ?
Nordmann et al. , J. Clin Microbiol. 2011.
Infection Carriage
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• Discover novel resistance determinants and their epidemiology - emergence worldwide in clinically-significant bacteria, mostly in
Gram- negative - Enterobacteriaceae Pseudomonas aeruginosa and Acinetobacter
baumannii (resistance to ß-lactams, fluoroquinolones, aminoglycosides…..)
• Understand genetics and biochemistry of antibiotic resistance determinants
• Develop novel diagnostic tools
• Evaluate and develop novel antibiotic molecules
ISI Web of Knowledge- Microbiology, 2011, P.Nordmann; 24 th /2682, #1 in France
Perspectives
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Conflits d’intérêt
• MC Ploy– bioMérieux, Sanofi Pasteur, GSK, Pfizer
• P Nordmann– bioMérieux, Becton Dickinson, Septeos,
Sanofi Aventis, GSK, Pfizer
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