Metallo-β-lactamase (MBL) project: From molecular biology to the development of an MBL-inhibitor

Transcription

1 Metallo-β-lactamase (MBL) project: From molecular biology to the development of an MBL-inhibitor Indo-Norwegian Workshop on Antimicrobial Resistance Tromsø, Norway th 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

2 BACKGROUND Pharma withdrawn from development of antibiotics Cost of development Restricted use Undervalued/underpriced Emergence of resistance New antibiotics or inhibitors of resistance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!

3 Molecular class β-lactamases Penicillins 1 st, 2 nd gen. cephalosporins 3 rd, 4 th gen. cephalosporins Monobactams Carbapenems 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 Inhibited by: A KPCs Boronic acid (clavulanic acid, tazobactam) D OXA-48 s: NaCl B MBLs, EDTA/Dipicolinic acid

4 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, Trimethoprimsulphamethoxazole etc.

5 KPC BACKGROUND: GLOBAL DISSEMINATION OXA-48 s VIM & NDM

6 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

7 MBL PROJECT IN TROMSØ Collaboration between microbiologists, biochemists, crystallographers and chemists National Reference Centre for Detection of Antimicrobial Resistance Norwegian Structural Biology Centre Collaborators: Institute of Pharmacy Dept. of Chemistry MarBio/MabCent International collaborators

8 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

9 NATIONAL REFERENCE CENTRE FOR DETECTION OF ANTIMICROBIAL RESISTANCE (K-res) Research Treatment options New antimicrobial strategies Molecular epidemiology Basic research on antimicrobial resistance Method development/ evaluation

10 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.

11 MBL PROJECT: RESEARCH ACTIVITIES Molecular biology Novel MBL inhibitor Drug Discovery

12 MBL PROJECT: MOLECULAR BIOLOGY RESEARCH Protein production Biochemical characterization Crystallization & structure determination Molecular modelling/docking studies

13 MBL PROJECT: MOLECULAR BIOLOGY RESEARCH VIM-7 AIM-1 GIM-1 VIM-26 Biochemical characterization: TMB-1, VIM-7-mutants, VIM-26, AIM-1-mutants, GIM-1-mutants Docking & QM/MM calculations:

14 MBL PROJECT: DRUG DISCOVERY VIM Marine extracts Chemical compounds ~3000 marine extracts screened ~40 synthesized chemical compounds

15 MBL PROJECT: POTENTIAL RESEARCH TOPICS Molecular biology: Characterization of novel carbapenemases Drug discovery: β-lactamase inhibitors Screening of chemical compounds Chemical synthesis

16 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