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    By Aalpesh Kachhadiya 2009H108403H

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    Lakshmi Indira
    The document discusses tuberculosis (TB), including that it is caused by Mycobacterium tuberculosis which primarily affects the lungs, describes current TB therapy and its limitations, and outlines various potential new drug targets in the TB drug development pipeline such as cell wall components, GTPases, the MEP pathway, and remodeling of existing antibacterial classes.

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    By Aalpesh Kachhadiya 2009H108403H

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    Lakshmi Indira
    59 views34 pages
    The document discusses tuberculosis (TB), including that it is caused by Mycobacterium tuberculosis which primarily affects the lungs, describes current TB therapy and its limitations, and outlines various potential new drug targets in the TB drug development pipeline such as cell wall components, GTPases, the MEP pathway, and remodeling of existing antibacterial classes.

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    The document discusses tuberculosis (TB), including that it is caused by Mycobacterium tuberculosis which primarily affects the lungs, describes current TB therapy and its limitations, and outlines various potential new drug targets in the TB drug development pipeline such as cell wall components, GTPases, the MEP pathway, and remodeling of existing antibacterial classes.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    59 views34 pages

    By Aalpesh Kachhadiya 2009H108403H

    Uploaded by

    Lakshmi Indira
    The document discusses tuberculosis (TB), including that it is caused by Mycobacterium tuberculosis which primarily affects the lungs, describes current TB therapy and its limitations, and outlines various potential new drug targets in the TB drug development pipeline such as cell wall components, GTPases, the MEP pathway, and remodeling of existing antibacterial classes.

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    -By

    Aalpesh Kachhadiya
    2009H108403H
    What is Tuberculosis?
    Infectious disease caused by the Mycobacterium
    tubercule species
    Primarily target lungs, but also kidney lung apices,
    bone marrow, kidneys, and meninges
    About 32% world’s population [2 billion people] are
    infected with TB.
    In India alone, one person dies of TB every minute.
    Types of tuberculosis:
     MDR tuberculosis
     XDR tuberculosis
     Latent tuberculosis
    Stages of M.tuberculosis Infection
    How Mtb tackle immune system?
    CURRENT TB THERAPY
    The treatment duration is a minimum of 6 months,
    with 4 drugs (isoniazid, rifampin, pyrazinamide, and
    ethambutol) typically given daily for the first 2
    months and with 2 drugs (isoniazid and rifampin)
    administered for 4 additional months.
    Compliance-the emergence of drug resistance.

    Potential for drug-drug interactions, primarily those


    between rifampin and many of the anti-HIV drugs.
    Current therapy:
    ISONIAZID

    AN T
    T
    RIFAMPIN

    E S I S
    R
    PYRAZINAMIDE

    ETHAMBUTOL

    STREPTOMYCIN
    Objectives for TB Drug Development:
    Simplify treatment/reduce treatment duration

    Have an acceptable toxicity profile

    Be an active against MDR/XDR TB

    Be useful in HIV –infected patients with TB

    Be active against latent TB

    No Drug –drug interaction


    Global TB Drug Portfolio
    September 2005
    Discovery Preclinical Clinical Testing

    Carboxylates Nitrofuranylamides Diamine SQ-109 Diarylquinoline TMC207


    TB Alliance, Wellesley College NIAID, University of Tennessee Sequella Inc. Johnson & Johnson

    Nitroimidazole Analogs Dipiperidines (SQ-609) Gatifloxacin


    Cell Wall Inhibitors
    NIAID, Novartis Institute for Tropical Diseases, OFLOTUB Consortium, Lupin, NIAID TBRU,
    Colorado State University, NIAID Sequella Inc.
    TB Alliance Tuberculosis Research Centre, WHO TDR

    Dihydrolipoamide Acyltransferase Non-Fluorinated Quinolone Moxifloxacin


    Novel Antibiotic Class Bayer Pharmaceuticals, CDC TBTC, Johns
    Inhibitors TaiGen
    GlaxoSmithKline, TB Alliance Hopkins University, NIAID TBRU, TB Alliance
    Cornell University, NIAID

    InhA Inhibitors Picolinamide Imidazoles Synthase Inhibitor FAS20013 Nitroimidazole PA-824


    GlaxoSmithKline, TB Alliance NIAID, TAACF) FASgen Inc. Chiron Corporation, TB Alliance

    Translocase I Inhibitors Nitroimidazo-oxazole OPC-67683


    Isocitrate Lyase Inhibitors (ICL) Pleuromutilins Sequella Inc., Sankyo Otsuka
    GlaxoSmithKline, TB Alliance GlaxoSmithKline, TB Alliance

    Macrolides Quinolones Nitroimidazo-oxazole Back-up Pyrrole LL-3858


    TB Alliance, University of Illinois at Chicago KRICT/ Yonsei University, NIAID, Otsukai Lupin Limited
    TAACF, TB Alliance

    Methyltransferase Inhibitors Screening and Target Identification


    Anacor Pharmaceuticals AstraZeneca

    Natural Products Exploration


    BIOTEC, California State University, ITR, NIAID, Thiolactomycin Analogs
    TAACF, University of Auckland NIAID, NIH
    M. Spigelman, GATB
    Newer therapy

    The American Journal of Medicine (2008) 121, 835-844


    MOA of New Drugs in clinical trial:
    Dormant Mtb target

    Active Mtb target

    Targets for/of New Anti-TB drug


    L,D-transpeptidase
    Two transpeptidase present:
    D,D transpeptidase-43linkage generation 
    Inhibited by β lactam antibiotics
    L,D transpeptidase – 33 linkage generation  80% of
    pepetide linkage
    Inhibition of both enzymes ,attenuated growth,virulence
    and ability to persist
    Also sensitized Mtb to amoxicillin-clavulanate –invitro
    and invivo
    GTPases:
     PI3K play essential role in
    maturation of phagosomes
     LAM: prevents PI3P generation
    on phagosomes
     SapM: act as PI3P phosphatase
    to remove this lipid from
    phagosomes
     Rab22a-member of family
    Rabs5(GTPase)-prevent
    phagosome maturation
     FtsZ-another assembling
    GTPase enzyme in Mtb
    MEP(2 C -methyl- D-erythritol 4-phosphate)
    Isoprenoid is essential which either functions as toxins,growth
    inhibitors or secondary metabolites
    Mtb isoprenoids:
     Pol-P “linkerunit” between two essential cell wall

    components,arabinogalactan and peptidoglycan


     Menaquinone:essential for electron transport chain

    All isoprenoids are derived from the repitive condensation of


    Isopentyl diphosphate and dimethylallyl
    diphosphate:synthesised only through MEP pathway
    Known inhibitors for MEP enzymes:
    Summary of targets:
    Remodeling of Existing antibacterial class
    References:
     Zhenkun Ma et.al- ‘Global tuberculosis drug development pipeline: the need and
    the reality’, Series: Tuberculosis 5
     Gyanu Lamichhane, ‘Review-Novel targets in M. tuberculosis : search for new drugs’,
    Cel Press
     Anil Koul et.al- ‘The challenge of new drug discovery for tuberculosis,
    Nature:Review’, doi:10.1038/nature09657
     Spigelman, ‘New Tuberculosis Therapeutics: A Growing Pipeline’, J Infect Dis.-2007
    ,S28-34
     Laxman S. Meena, Review:”Guanosine triphosphatases as novel therapeutic targets in
    tuberculosis”, International Journal of Infectious Diseases 14 (2010) e682–e687
     Hyungjin Eoh, Review:”The Mycobacterium tuberculosis MEP (2 C -methyl- D-erythritol
    4-phosphate) pathway as a new drug target”, Tuberculosis 89 (2009) 1–11
     Jossy van den Boogaard, Minireview: ” New Drugs against Tuberculosis: Problems,
    Progress, and Evaluation of Agents in Clinical Development”, ANTIMICROBIAL
    AGENTS AND CHEMOTHERAPY, Mar. 2009, p. 849–862
      Working group on New TB Drug: http://www.newtbdrugs.org/project.php?id=25, date-
    24th April 2011
    Change of target:GSK and TB alliance
    The glyoxylate pathway uses isocitrate lyase (ICL) and
    malate synthase to incorporate carbon during growth
    of microorganisms on acetate or fatty acids as the
    primary carbon source.
    ICL:project was discontinued due to lack of
    druggability of the ICL targets.
    Structural analysis indicated that malate synthase is a
    much more druggable target by virtue of its deeper
    and more hydrophobic binding domain.
    Mycolic acid cyclopropanation:
    Mycolic acid :Major constitute of cell wall

    Cyclopropanation require to unite different mycolic acid

    molecule
     Multiple iso-enzymes present.

    Dioctylamine : broad inhibition of cyclopropanation-

    bacteriostatic at 6μM
    DprE1/DprE2:
    DprE1 heterodimerizes with DprE2 to form active enzyme
    Converts : to incorporate into the cellwall
    decaprenylphosphoryl ribose decaprenylphosphoryl
    arabinose
    Inhibitor: BTZ043 (1-4ng/ml)- benzothiazinone class
    : Dinitrobenzamides
    Showed similar potency in various strain of TB:
     Drug sensitive
     XDR

     MDT

     extensively resistant strain


    Mycothiol ligase:
    Mycothiol, low molecular weight thiol that protects Mtb from
    toxicity of antibiotics and oxidative stresses

    Dequalinium chloride
    High affinity
    Inhibition of growth :0.3-1.2μg/mL
    ATP phosphoribosyl transferase:
    Histidine biosynthesis pathway enzymes
    Histidine essential for the growth of Mtb
    Conversion of:

    5 –phospho-α-D-ribose 1- HisG L- Histidine


    diphosphate

    Inhibited by:
    Nitrobenzothiazole Phosporibosyl -ATP
    ATP synthase:
    Involve in the synthesis of ATP

    Diaryl quinoloine compound(R201910):Affinity for the α & β

    subunit of the enzyme.


    Inhibit the enzyme in dose dependent manner

    Active in dormant and drug resistant strain also

    20,000 times less affinity for Human ATP synthase

    Currently in Clinical trials designated asTMC-207


    Protein processing: deformylase and methionine
    aminopeptidase
    mRNA translation begins with the incorporation of formylated

    methionine at the amino (N) terminus.

    This residue is removed in a two-step process:

    o deformylation by peptide deformylase

     Inhibitor: LBK-611 displayed a MIC in the micromolar range

    o hydrolysis of methionine by methionine aminopeptidase

     Inhibitor: 2,3-dichloro-1,4 napthoquinones

     Human beings are devoid of above enzyme, hence good target for anti-TB activity
    Isocitrate lyase:
    Role: fatty acid synthesis, virulence characteristics
    Inhibitor: 3-nitro-propionate
    Inhibition of isocitrate lyase activity causes genetic
    loss of icl1 and icl2 gene.
    Results into loss in ability to:
     Grow in fatty acids,
     Loss of virulence
     Growth defect during acute and chronic phase of
    infection

    Recent news:
    The Proteasome complex:
    Role: degradation of oxidized proteins,
    Proteasome activity required to maintain infection
    during chronic phase
    Morphology:
     Accessory ATPase enzyme associated with
    proteoasome Mpa.
     Presence of catalytically active site threonine residue
     Inhibitor:
     Threonine site : Oxathiazol-2-one
    Synergizes with the immune control of Mtb infection
    DosR(DevR)
    After engulfment by macrophage, Mtb experience
    hypoxia and stress condition(NO)
    Hence increased levels of DosR(DevR) which are
    transcription factor, that binds to major groove of
    DNA as a tetramer – activates dormancy regulon
    physiological adaption
    Presence of 48 genes
    Inhibition of DosR alone might be effective in
    controlling growth or have synergistic effects with
    other anti-TB drug
    Maltosyltransferase GlgE
    Accumalation of Maltose-1-phosphate is toxic to Mtb
    Adversely affect the Electron transport chain .
    GlgE utilizes maltose-1-phosphate to elongate 1,4-
    glucan chains.
    Transcriptional profile was similar to that elicited by
    Pot.cyanide
    Gut flora and mammals lack proteins homologous to
    GlgE ,hence suitable drug target

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