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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

Iraq

Switzerland

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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