the zinchel project - overcoming -lactam resistance rongved.pdf · silver ll. clin. microbiol. rev....
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The Zinchel Project
Oslo, May 2016
Pål Rongved
The ZinChel Project - Overcoming β-Lactam
Resistance
Background, results and plans
Contents:
• Background: the post-antibiotic era – why are we loosing?
• What is the ZinChel technology?
• Results
• Specific tasks to investigate resistance and mechanism of action
• Plans and budget
• The link to HORIZON2020 and other EU initiatives
• People and project team
• Summary
Background
Bacteria – the first cells on earth?
Ancient Fossil Bacteria : Pictured above are two kinds cyanobacteria from
the Bitter Springs chert of central Australia, a site dating to the Late
Proterozoic, about 850 million years old. On the left is a colonial
chroococcalean form, and on the right is the filamentous Palaeolyngbya.
Sources: Bitter Springs chert fossil image provided by J. William Schopf. Image of stromatolites provided by the University of
Wisconsin Botanical Images Collection
• The oldest known fossils: cyanobacteria from Archaean rocks of
western Australia, dated 3.5 billion years old.
• The oldest rocks: a little older: 3.8 billion years old!
• Milton Mainwright, Sheffield University “Imhokep, the notable ancient
Egyptian healer, (….) is known to have treated surface infections with
mouldy bread“,
• In 1874: Sir William Roberts: cultures of the mold with Penicillium
glaucum was antibacterial.
Gorgonzola,
an Italian
cheese
containing
"veins" of
Penicillium
glaucum
Statuette of Imhotep
in the Louvre
Drug Discovery within Antibiotics (AB)
Penicillinase: bacterial weapon destroying the AB
1940 – first penicillinase discovered
1942 – first penicillin became «available»
Carbapenems:
One of the last resort AB’s today The first one, Imipenem. FDA approved
1985.
Metallo-β-lactamases (MBL): new, more
efficient new penicillinases: first crystal
structure solved in 1995
Alexander Fleming: penicillin G in 1928
- the 1945 Nobel Price in medicine
Silver LL. Clin. Microbiol. Rev. 2011
CDC 2013
Ampicillin, Piperacillin-tazobactam, Mecillinam, Cefotaxim,
Ceftazidime, Meropenem, Imipenem, Ciprofloxacin, Levofloxacin,
Gentamicin, Tobramycin, Azitromycin, Tigecyline, Colistin,
Fosfomycin, Trimetoprim-sulfamethoxazole, Tetracycline,
Chloramphenicol, Temocillin, Nitrofurantoin, Amoxicillin, Oxacillin,
Ticarcillin, Cefepime, Doripenem, Aztreonam, Ceftobiprole,
Cefalexin, Ertapenem, Amikacin, Netilimicin, Vancomycin,
Telavancin, Norfloxacin, Erytromycin, Clindamycin, Minocycline,
Daptomycin, Spectinomycin…….etc…..etc….etc….etc…..
Why are we loosing?
• Polymyxin (colistin) resistance: singularly due to the plasmid-carried mcr-1 gene.
• Readily transmissable
• Plasmid transfer possible also to Klebsiella pneumoniae and Pseudomonas aeruginosa
• mcr-1 encodes a phosphoethanolamine transferase (zinc dependent enzymes)
• “Findings emphasize the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria”
China autumn 2015: the fall of a last resort antibiotic The mcr-1 gene for polymyxin resistance on the run..
Liu et al, Lancet Infect Dis 2015
Horizontal gene transfer
between different species
• The most threatening bacteria today: the
Gram negatives
• In 30 years: only two genuinely first-in-class
AB to the market (US)
• None against Gram negatives!
What new Antibiotics (AB) are marketed?
Dalbavancin
(EU: Xydalba, Actavis)
Newly discovered:
Teixobactin Ling et al, Nature L517 (2015) 455
The ZinChel project Discovery and results
The ZinChel project – a new strategy against resistant bacteria
Based on chemistry – rational design
How penicillins work: Mechanism of action (MOA) β-lactams:
Our approach:
How carbapenemases work: ZINC!
PCT Examiners
patentability report 2015:
No-one else is working
with the same:
Results
ZinChel Results – Testing Clinically Relevant Resistant Bacteria (Ø. Samuelsen, UNN)
ZN41
IC50: 7,7µM
ZN53
IC50: 1,8µM
ZN58
IC50: 0,4µM Activity against
pure enzyme
(VIM-2)
Results Clinical Isolates
ID, bacterial strain
MIC (mg/L)
K34-7 K66-45
Name, bacterial strain/cell type
P. aeruginosa K.
pneumoniae
Inhibitor concentration: 125 µM
β-Lactamase VIM-2 NDM-1
MEM 32-64 32
ZN74 >1000 >1000
ZN110 >1000 >1000
TPEN >1000 500
MEM + ZN74 2 ≤ 0,125
MEM + ZN110 2 0,5
MEM + TPEN 1 ≤ 0,5
MEM + Captopril 32 64
Meropenem
(MEM) Captopril
Results Clinical Isolates
ID, bacterial strain
MIC (mg/L) IC50 (µM)
K34-7 K66-45 Human Cancer Cells (µM) Healthy human
cells
Name, bacterial strain/cell type
P. aeruginosa K.
pneumoniae
Breast cancer Pancreas cancer
hepG2 Inhibitor concentration: 125µM MDA-MB-231 MiaPaCa Colo357
β-Lactamase VIM-2 NDM-1 n.a. n.a. n.a. n.a.
MEM 32-64 32 n.a. n.a. n.a. n.a.
ZN74 >1000 >1000 4.9 ± 0.7 4.8 ± 1.2 6.8 ± 1.4 ~ 100
ZN110 >1000 >1000 101 ± 21 66 ± 13 112 ± 33 >> 100
TPEN >1000 500 2.5 ± 0.7 3.5 ± 2.2 2.9 ± 1.1 ~ 10
MEM + ZN74 2 ≤ 0,125 n.a. n.a. n.a. n.a.
MEM + ZN110 2 0,5 n.a. n.a. n.a. n.a.
MEM + TPEN 1 ≤ 0,5 n.a. n.a. n.a. n.a.
MEM + Captopril 32 64 n.a. n.a. n.a. n.a.
Meropenem
(MEM) Captopril
Results Clinical Isolates
ID, bacterial strain
MBL-positive Gram-negatives
P. Aeruginosa (K34-7) – VIM-2 K. Pneumoniae (K66-45) - NDM1
Conc. inhibitor(µM) 50 31,3 15,6 50 31,3 15,6
MEM+ZN141 1 1 32 0,125 0,125 16
MEM+ZN142 1 2 16 0,125 0,125 8
MEM+ZN144 1 2 32 0,125 0,125 16
MEM+ZN145 1 1 4 0,25 0,125 4
MEM+ZN147 2 2 32 0,125 0,125 16
MEM+ZN148 1 1 16 0,125 0,125 8
MEM+ZN155 1 4 32 0,125 4 16
MEM + TPEN 1 ≤ 0,5 n.a. n.a. n.a. n.a.
MEM + Captopril
32 64 n.a. n.a. n.a. n.a.
Meropenem
(MEM)
Captopril
Results - hematology
Tromsø, February 2016:
No colorization in red blood
cell suspensions in
concentretions of lead
candidates < 500 µM
Jim O’Neill, 2016:
Ongoing work
Microbe-targeted
Zn-chelators
(as for other AB
projects)
Toxicity?
• Cell lines
• Animal
models
Efficacy?
Resistance
development?
Mechanism of
action? • β-lactamases?
• PBPs?
• Other Zn-dependent
enzymes?
• Zn-homeostasis?
Project plan
Dr Ørjan Samuelsen
Dag Berild, et al OUS
Opportunities
Horizon2020 – IMI – ND4BB ZinChel Spring 2015: open invitation into the IMI programme
ENABLE
• IMI: the world's biggest
public-private partnership
(PPP) in the life sciences.
• IMI 2 programme: €3.3
billion budget 2014-2024.
Of this:
• €1.638 billion comes from
Horizon 2020
• €1.425 billion is committed
to the programme by
EFPIA companies
• Up to €213 million can be
committed by other life
science industries or
organisations that decide
to contribute to IMI 2 as
members or Associated
Partners in individual
projects
Horizon2020
Summary
• Only two genuinely new classes of antibiotics in 30 years
• Industry is reluctant because of rapid development of resistance.
• ZinChel: genuinely new adjuvant technology, dramatically reducing resistance.
• ZinChel make the carpapenems efficient again (resistant clinical isolates).
• The scope of the ZinChel approach: very wide.
• Not based on natural products but on medicinal chemistry rational design.
• Key studies ongoing: resistance potential and in vivo tox.
• An open door to EU through the IMI/Enable programme.
People
Associate Professors
Annette Bayer
Dr Hanna-Kirsti Leiros
Postdoc Zeeshan Mohamad
Dr Ørjan Samuelsen
Postdoc Silje Lauksund
O. Alexander H. Åstrand
Scientist Geir Kildahl-Andersen
Scientist Christian Schnaars
PhD student Elvar Ø. Viktorsson
MSc student Ørjan Apeland
PhD student Anthony Prandina
Associate Professor Lars Petter Jordheim
Funding:
Center for Integrative
Microbial Evolution, UiO
CIME PhD
student
Anthony
Prandina
Centre for Integrative
Microbial Evolution
(CIME), UiO
CIME PhD student
Anthony Prandina
Hanne Winther-Larsen
Mike Koomey
Tom Kristensen
Dirk Linke
Ole Andreas Økstad
People
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Thank you for your attention…