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Metallo-β-lactamase (MBL) project: From molecular biology to the development of an
MBL-inhibitor
Indo-Norwegian Workshop on Antimicrobial Resistance Tromsø, Norway
26-27th of September 2013
Ørjan Samuelsen Reference Centre for Detection of Antimicrobial Resistance
Dept. of Microbiology and Infection Control University Hospital of North Norway
Tromsø, Norway
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Pharma – withdrawn from development of antibiotics
Cost of development
Restricted use
Undervalued/underpriced
Emergence of resistance
New antibiotics or inhibitors of resistance mechanisms are urgently needed!
BACKGROUND
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BACKGROUND: CARBAPENEMASES
• Carbapenemase: β-lactamases that inactivates carbapenems
Serine β-lactamases Metallo-β-lactamases (MBLs)
Class A Class D Class B
β-lactam substrates β-lactamase inhibitors
Mo
lecu
lar
clas
s
β-l
acta
mas
es
Pen
icill
ins
1st
, 2n
d g
en
. ce
ph
alo
spo
rin
s
3rd
, 4th
ge
n.
cep
hal
osp
ori
ns
Mo
no
bac
tam
s
Car
bap
enem
s
Inhibited by:
A KPCs + + + + + Boronic acid
(clavulanic acid, tazobactam)
D OXA-48’s: + + - - + NaCl
B MBLs, + + + - + EDTA/Dipicolinic acid
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BACKGROUND: THE EMERGENCE OF CARBAPENEMASES IN GRAM-NEGATIVE PATHOGENS
• Major carbapenemases:
– Class A: KPC
– Class B (MBLs): NDM, VIM, IMP
– Class D: OXA-carbapenemases
• Enterobacteriaceae, P. aeruginosa and A. baumannii
• →Co-resistance
– Aminoglycosides, Fluoroquinolones, Trimethoprim-sulphamethoxazole etc.
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BACKGROUND: GLOBAL DISSEMINATION
KPC OXA-48’s
VIM & NDM
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BACKGROUND: RAPID GLOBAL DISSEMINATION
• Example: New Dehli Metallo-β-Lactamase (NDM)
• Sweden (India) 2008: K. pneumoniae
• Retrospective analysis: 2006 India
• >40 countries • “Promiscuous” plasmids
• Diversity of clones
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MBL PROJECT IN TROMSØ
• Collaboration between microbiologists, biochemists, crystallographers and chemists
• Collaborators: – Institute of Pharmacy
– Dept. of Chemistry
– MarBio/MabCent
– International collaborators
National Reference Centre for Detection of Antimicrobial Resistance
Norwegian Structural Biology Centre
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National Reference Centre for Detection of Antimicrobial Resistance (K-res)
• Dept. of Microbiology and Infection Control
• Close collaboration with research groups at UiT
• Main funding: Ministry of Health
– 4,2 positions (20% M.D., 2 scientists, 2 technicians)
• Primary objectives:
– Phenotypic & molecular analysis
– Competence building
– Research
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NATIONAL REFERENCE CENTRE FOR DETECTION OF ANTIMICROBIAL RESISTANCE (K-res)
• Research
Molecular epidemiology
Treatment options
Basic research on
antimicrobial resistance
Method development/
evaluation
New antimicrobial
strategies
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NORWEGIAN STRUCTURAL BIOLOGY CENTRE (NORSTRUCT)
• National research and service centre
• State of the art instrumentation from protein production through high throughput crystallization and structure determination to drug discovery related tasks.
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MBL PROJECT: RESEARCH ACTIVITIES
Molecular biology
Drug Discovery
Novel MBL inhibitor
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MBL PROJECT: MOLECULAR BIOLOGY RESEARCH
• Protein production
• Biochemical characterization
• Crystallization & structure determination
• Molecular modelling/docking studies
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MBL PROJECT: MOLECULAR BIOLOGY RESEARCH
• Biochemical characterization: – TMB-1, VIM-7-mutants, VIM-26, AIM-1-mutants, GIM-1-mutants
• Docking & QM/MM calculations:
VIM-7 AIM-1 GIM-1 VIM-26
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MBL PROJECT: DRUG DISCOVERY
Marine extracts
Chemical compounds
VIM
~3000 marine extracts screened ~40 synthesized chemical compounds
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MBL PROJECT: POTENTIAL RESEARCH TOPICS
• Molecular biology:
– Characterization of novel carbapenemases
• Drug discovery:
– β-lactamase inhibitors
– Screening of chemical compounds
– Chemical synthesis
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Hanna-Kirsti S. Leiros, Annette Bayer, Susann Skagseth, Bjarte Aarmo Lund, Gro Bjerga, Tony Christopheit, Trine Josefine Olsen Carlsen, Arne Smalås
Ørjan Samuelsen, Arnfinn Sundsfjord
Pål Rognved, Ove Alexander Åstrand
James Spencer
Timothy Walsh
Rafi Ahmad