The ZinChel Project - Overcoming -Lactam Resistance LL. Clin. Microbiol. Rev. 2011 CDC 2013...

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Transcript of The ZinChel Project - Overcoming -Lactam Resistance LL. Clin. Microbiol. Rev. 2011 CDC 2013...

  • The Zinchel Project

    Oslo, May 2016

    Pl Rongved

    The ZinChel Project - Overcoming -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

    http://www.ucmp.berkeley.edu/bacteria/origin5.gifhttp://www.ucmp.berkeley.edu/precambrian/bittersprings.htmlhttps://en.wikipedia.org/wiki/File:Gorgonzola_1.jpghttps://en.wikipedia.org/wiki/Gorgonzola_(cheese)https://en.wikipedia.org/wiki/File:Imhotep-Louvre.JPGhttps://en.wikipedia.org/wiki/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 ABs today The first one, Imipenem. FDA approved

    1985.

    Metallo--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) -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 (. Samuelsen, UNN)

    ZN41

    IC50: 7,7M

    ZN53

    IC50: 1,8M

    ZN58

    IC50: 0,4M 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 M

    -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 (M)

    K34-7 K66-45 Human Cancer Cells (M) Healthy human

    cells

    Name, bacterial strain/cell type

    P. aeruginosa K.

    pneumoniae

    Breast cancer Pancreas cancer

    hepG2 Inhibitor concentration: 125M MDA-MB-231 MiaPaCa Colo357

    -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(M) 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

    Troms, February 2016:

    No colorization in red blood

    cell suspensions in

    concentretions of lead

    candidates < 500 M

  • Jim ONeill, 2016:

  • Ongoing work

  • Microbe-targeted

    Zn-chelators

    (as for other AB

    projects)

    Toxicity?

    Cell lines

    Animal

    models

    Efficacy?

    Resistance

    development?

    Mechanism of

    action? -lactamases?

    PBPs?

    Other Zn-dependent

    enzymes?

    Zn-homeostasis?

    Project plan

    Dr rjan 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 rjan Samuelsen

    Postdoc Silje Lauksund

    O. Alexander H. strand

    Scientist Geir Kildahl-Andersen

    Scientist Christian Schnaars

    PhD student Elvar . Viktorsson

    MSc student rjan 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 kstad

    People

  • 26

    Thank you for your attention