Transcript Multidrug resistance

Resistance to Antibiotics
Emerging threats and New molecular targets
Marie-Cécile Ploy
Patrice Nordmann
Avenir Inserm
Limoges University, France
U 914 Inserm
South-Paris Medical School,
K-Bicêtre, France
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Antibiotic resistance
• Worldwide public health issue
• All antibiotic families are concerned
• Infections difficult to treat
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Fighting the resistance
• Good practices in antibiotic prescription
• Hygiene procedures
Improve knowledge on antibiotic resistance acquisition
Genetics, dissemination, detection
New therapeutic strategies to fight the resistance
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Stressful conditions
including
Antibiotics
Bacterial SOS response
Expression
of resistance genes
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Mutations
of resistance
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Mobilization
of mobile elements
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Gene dissemination accounts for 80%
of clinical resistances
Horizontal
Gene
Transfer
ENVIRONMENT
Water, Soils, …
CONTACT
ANIMAL
HUMAN
Food
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Gene dissemination relies on diverse genetic
vehicles
a
plasmids
tranposon
aintegron
ATB
Induce the SOS response
a
Gene transfer
Induces the SOS response
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Specific role of Integrons in antibiotic resistance
Pc
intI
attI
Cassette
Pc
attC1
intI
LexA
-35
intI
Stress /
-10
Pint
attC1
SOS response
Site
LexA
LexA
ssDNA-RecA
-35
Antibiotics
intI
-10
Pint
Site
LexA
IntI
Science 2009, Mobile DNA 2011
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From resistance to susceptibility:
search for inhibitors
LexA
intI
ATB stress
-10
attI
-35
Pint
Inhibition of SOS
response
SOS system
LexA
ssDNA-RecA
Global effect on
IntI1 expression
and horizontal
gene transfer
attI
intI
-10
-35
Pint
LexA
Binding site
IntI1
active protein
Inhibition of integrase
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Inhibition of gene
cassettes
acquisition
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Perspectives
Importance of SOS response in antibiotic resistance
Antibiotic-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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Multidrug resistance : a major public health
issue; 2011 update
Hospital
Community
Methicillin-resistant Staph
Vancomycin-resistant enterococci
P. aeruginosa
Multidrug resistance
A. baumannii
pandrug resistance
Enterobacteriaceae
Extended-spectrum β-lactamases
Enterobacteriaceae
Carbapenemase
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Multidrug resistance : a major public health
issue; 2011 update
Hospital
Community
Methicillin-resistant Staph
Vancomycin-resistant enterococci
P. aeruginosa
Multidrug resistance
A. baumannii
pandrug resistance
NDM-1 superbugs
Enterobacteriaceae
Extended-spectrum β-lactamases
Enterobacteriaceae
Carbapenemase
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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
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Kumarasamy et al., Lancet Infect. Dis. 2010, 10:597
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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 communityacquired infections
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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
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The genetics of blaNDM-1
ΔISAba125
blaNDM-1
ISEC33
bleomycin ΔPh.ribosyl
resistance anthranilate
protein
isomerase
ISSen4
Escherichia coli
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The genetics of blaNDM-1 :from A. baumannii to E. coli
ΔISAba125
blaNDM-1
ISEC33
bleomycin ΔPh.ribosyl
resistance anthranilate
protein
isomerase
blaNDM-1
ISAba125
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bleomycin
resistance
protein
INRIA
ISSen4
Escherichia coli
ISAba125
A. baumannii
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The epidemic of NDM-1 producers
Morocco
Egypt
Iraq
Switzerlan
d
Spai
n
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The epidemic of NDM-1 producers
Morocco
Egypt
Iraq
Identification
Switzerla
nd
10 hotspots of NDM-1
producers; the usefulness
of an international
network (labs, n= 36)
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How to detect NDM-1 producers ?
Infection
Carriage
Screening
of carrriers (stools)
ESBL screening medium
Susceptibility testing
(Automated systems, disk diffusion, )
Molecular identification of
carbapenemase genes
Nordmann et al. , J. Clin Microbiol. 2011.
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Perspectives
• Discover novel resistance determinants and their epidemiology
- emergence worldwide in clinically-significant bacteria, mostly in Gramnegative
- 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
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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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