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A L I M E N T A T I O N
A G R I C U L T U R E
E N V I R O N N E M E N T
Salmonella Genomic Island 1: Succès d’un îlot génomique de multirésistance à travers
ces dernières décennies
Journée Anses sur l’antibiorésistance en santé animale
Maisons-Alfort, 19 novembre 2012
Benoît Doublet INRA-Université François Rabelais de Tours
UMR1282-Infectiologie et Santé Publique
Nouzilly, France
Epidemic Salmonella enterica serovar Typhimurium DT104
Multidrug resistant S. Typhimurium DT104 clone
1st isolation in early 80’s (gulls, exotic birds) and late 80’s (human and cattle) (UK)
Global spread 1990s (animal and human)
Pentadrug resistance profile (ACSSuT):
Ampicillin, Choramphenicol / Florfenicol, Streptomycin / Spectinomycin
Sulfonamides, Tetracyclines
Identification of a chromosomal antibiotic resistance gene cluster (1999)
A complex class 1 integron: In104
tnpR intI1 aadA2
qacE∆1
sul1∆ floR tetR tet(G) orf1 orf2
groEL/intI1
blaPSE-1
qacE∆1
sul1
orf5
orf6 IS6100
S044
IRi IRt IRt
In104
SGI1 Episode 1: The Past
Recombination
Transfer
Regulation
Antibiotic resistance
Other function
Replication
Unknown function
43 kb
Integration site: at the 3’ end of trmE
Flanked by DR-L et DR-R
Complex integron In104
SGI1 Episode 1: The past
trmE
SGI1 and Salmonella Spread and genetic plasticity
Agona
Albany
Anatum
Cerro
Choleraesuis
Derby
Dublin
Düsseldorf
Emek
Haifa
Infantis
Kedougou
Kentucky
Kiambu
Kingston
Kottbus
Mbandaka
Meleagridis
Newport
Ohio
Paratyphi B
Schleissheim
Tallahassee
Typhimurium
Virchow
SGI1 (ACSSuT)
SGI1-A (ACSSuTTm)
SGI1-B (ASu)
SGI1-C (SSu)
SGI1-D (SSuTm)
SGI1-E (ASSuT)
SGI1-F (ACSuTTm)
SGI1-G (ASuTm)
SGI1-H (ACGSSuT)
SGI1-I (CSSuTTm)
SGI1-L1 (ACGSSuTTm)
SGI1-L2 (ACGSSuTTm)
SGI1-M (ACGKSuTTo)
SGI1-R (ACST)
SGI1-S (AkGKSuTmTo)
SGI1-T (CST)
SGI1-J1 (CSuTTm)
SGI1-J2 (SuTm)
SGI1-J3 (CSuTTm)
SGI1-J4 (Su)
SGI1-J5 (CSuTTm)
SGI1-J6 (CSSuT)
SGI1-K1 (AGSSuT)
SGI1-K2 (ASSuT)
SGI1-K3 (AGSSuT)
SGI1-K4 (GSSuT)
SGI1-K5 (GSSu)
SGI1-K6 (AGSSuT)
SGI1-Ps (A)
SGI1-Qs (Ø)
SGI1 Integron genetic plasticity
SGI1 ACSSuT
(Boyd et al., 2000) intI1 aadA2 qacE∆1
sul1∆ floR tetR tet(G) orf1 orf2
groEL/intI1
blaPSE-1 qacE∆1
sul1 orf5 orf6
IRi IRt IRt
ISCR3
IS6100
SGI1-A ACSSuTTm
(Boyd et al., 2002) dfrA10 orf513
ISCR1
qacE∆1 sul1 orf5 orf6
IRi IRt IRt
intI1 aadA2
qacE∆1
sul1∆ floR tetR tet(G) orf1 orf2 groEL/intI1
blaPSE-1 qacE∆1
sul1
ISCR3
IS6100
IRi
SGI1-H ACGSSuT
(Doublet et al., 2004)
ISCR3
IRt IRt
qacE∆1
sul1∆ floR tetR tet(G) orf1 orf2
groEL/intI1
blaPSE-1 qacE∆1
sul1 orf5 orf6 intI1 aac(3)-Id aadA7 IS6100
SGI1-K1 AGSSuT
(Levings et al., 2007 ;
Doublet et al., 2008)
IRi
intI1 aac(3)-Id aadA7 qacE∆1
sul1 orf5
IRt IR-Tn21
E D A C P T R
gènes mer
Tn21
tetR tet(A) tnpA pecM
IRRII-Tn1721
IRR-Tn5393
Tn1721
res
IRR-Tn3
Tn5393
strB strA
IS1133
tnpR∆
IS26
tnpR blaTEM-1
IS26
S044∆
Tn3
Tn5393 IS6100
ISCR3
IS26
tnpR blaTEM-1
IS26
S044∆
Tn3
IRi res IRR-Tn3
SGI1-Ps A
(Doublet et al., 2008)
IS26
S044∆
IRi
SGI1-Qs Ø
(Doublet et al., 2008) intI1∆ In, IS, Tn are genetic weapons to acquire resistance genes
SGI1 Episode 2: The Present
Emerging multidrug-resistant
clone S. Kentucky ST198
SGI1 in MDR S. Kentucky ST198
res intI1 aadA7
qacE 1
sul1
orf5∆
IS6100
IRi IRt
SGI1-K1 MDR cluster: A mosaic structure
aac(3)I-d orf2
E D A C P T R
mer genes
IR-Tn21
tetR tet(A)
S044
yidY
DR-R
IS26 blaTEM-1 tnpR IS26
tnpR
IS1133 strA pecM tnpA strB
IRRII-Tn1721 IRR-Tn5393 res IRR-Tn3
In4-type integron Tn21
Tn1721
Tn5393
Tn3
Tn5393
0 5 10 15 20 24 kb
Poultry: important vehicle to spread
Fluoroquinolone use in chicken and
Turkey
Integrated aquaculture Poultry
Aquatic ecosystem in the acquisition
of SGI1
?
SGI1 in MDR S. Kentucky ST198
Africa
Asia
2 geographic sub-populations
res S026 S025 S023 S024
SGI1
backbone S044
Transpositional site of all In104 and
derivatives (except InSGI1-Js)
All SGI1-positive serovars, Worldwide
DR-R
yidY trmE
(thdF)
DR-L
int xis
CCATG
Transpositional site of InSGI1-Js
Serovars Emek, Virchow, and Kentucky ST198
Southeast Asia
S005∆
S009∆
ISVch4
orfB orfA
5340 8120
S010
SGI1-Ks, -Ps, -Qs Serovar Kentucky ST198-X1 Africa
ACTTG
SGI1-Js Serovar Kentucky ST198-X2 Southeast Asia
ISSen5
CTA TAG
S023
SGI1-Ks, -Ps, -Qs Serovar Kentucky ST198-X1 Africa
S044 IS26
SGI1 in MDR S. Kentucky ST198
2 different SGI1 variants
Genetic plasticity extend outside the complex integron in SGI1
Africa
Asia
SGI1 and Salmonella Horizontal gene transfer ?
Agona
Albany
Anatum
Cerro
Choleraesuis
Derby
Dublin
Düsseldorf
Emek
Haifa
Infantis
Kedougou
Kentucky
Kiambu
Kingston
Kottbus
Mbandaka
Meleagridis
Newport
Ohio
Paratyphi B
Schleissheim
Tallahassee
Typhimurium
Virchow
SGI1 (ACSSuT)
SGI1-A (ACSSuTTm)
SGI1-B (ASu)
SGI1-C (SSu)
SGI1-D (SSuTm)
SGI1-E (ASSuT)
SGI1-F (ACSuTTm)
SGI1-G (ASuTm)
SGI1-H (ACGSSuT)
SGI1-I (CSSuTTm)
SGI1-L1 (ACGSSuTTm)
SGI1-L2 (ACGSSuTTm)
SGI1-M (ACGKSuTTo)
SGI1-R (ACST)
SGI1-S (AkGKSuTmTo)
SGI1-T (CST)
SGI1-J1 (CSuTTm)
SGI1-J2 (SuTm)
SGI1-J3 (CSuTTm)
SGI1-J4 (Su)
SGI1-J5 (CSuTTm)
SGI1-J6 (CSSuT)
SGI1-K1 (AGSSuT)
SGI1-K2 (ASSuT)
SGI1-K3 (AGSSuT)
SGI1-K4 (GSSuT)
SGI1-K5 (GSSu)
SGI1-K6 (AGSSuT)
SGI1-Ps (A)
SGI1-Qs (Ø)
SGI1 MDR Integrative Mobilisable Element
0 20 30 10 40
42,433
kb
TTCTGTATTGGGAAGTAA
Extrachromosomal
circular intermediate of
SGI1
TTCTGTATTGGTAAGTAA
trmE
SGI1 site-specific sequence (attP)
3’ end of trmE (attB site)
trmE
Chromosomal
inserted SGI1
yidY (S. enterica)
tnaL (E. coli)
In104 integron int
yidY (S. enterica)
tnaL (E. coli)
SGI1-encoded
Integrase
DR-L DR-R
Site-specific
excision/integration
Conjugative transfer
by mobilization in trans
SGI1 MDR Integrative Mobilisable Element
Conjugative IncA/C2 MDR plasmids (blaCMY-2, blaNDM-1,...) IncA/C MDR plasmids in fish pathogens Environmental MDR dissemination in aquatic ecosystem
IncA/C2 pR55
IncA/C1 pRA1
IncA/C2 pIP1202
IncA/C2 pR55
IncA/C2 pSN254
IncA/C2 pNDM-1_Dok01
SGI1 Episode 3: The Future...
SGI1 in other bacteria: Proteus mirabilis
First isolate in 2006 (Palestine, diabetic foot infection) Ahmed et al. 2007
Human and food isolates (China, 2007) Boyd et al. 2008
First French SGI1 Proteus mirabilis cases
A public Health concern ?
SGI1-V AkGKNeSSuToTm(ESBL, FQ)
(Siebor et al., 2011) dfrA1 orf513
ISCR1
qacE∆1 sul1 orf5 orf6
IRi IRt IRt
intI1 aacA4 tnpRΔ5’ tetA(A)Δ5’ orfC blaVEB-6
qacE∆1
sul1 IS6100 qnrA1 orf orf
qacE∆1
sul1 aadB
ESBL phenotype Low level FQ resistance
SGI1-S AkGKSuTmTo
(Wilson et al., 2010)
IRi
dfrA1 orfC intI1 sul1
qacE∆1
orf5∆ rmtC ISEcp1∆
ISKpn14
aacC2
ISCfr1
E D A F P T R
gènes mer
Tn512
tniB∆ tniA
IRt
IRi512 IRmer
tniQ tniR tniB tniA
IRt512
Tn402
S044
SGI1 Episode 3: The Future...
An actual clinical hazard in the near future?
SGI1-S from S. enterica serovar Virchow strain SL491
SGI1 Episode 3: The Future...
Establishment of SGI1+-CIPR Kentucky ST198 in Poultry in Europe ?
Chickens in Belgium ?
SGI1 Not the End...
ISP, Brussels, Belgium
Sophie Bertrand
Jean-Marc Collard
ANSES, Maisons-Alfort, France
Anne Brisabois
Sophie Granier
CERVA, Brussels, Belgium
Patrick Butaye
ANSES, Lyon, France
Jean-Yves Madec
Institut Pasteur, Paris, France François-Xavier Weill
Simon Le Hello
Laetitia Fabre
Agricultural Biotechnology Centre, Hongrie Ferenc Olasz
Janos Kiss
National Microbiology Laboratory, Public Health
Agency of Canada Michael R. Mulvey
David A. Boyd
INRA, Nouzilly, France Axel Cloeckaert
Karine Praud
Gregory Douard
Chang Gung Children’s hospital, Taiwan
Cheng-Hsun Chiu
National Chiayi University, Taiwan
Chishih Chu
INSERM U914, Paris, France
Laurent Poirel