Sonderforschungsbereich 630

    B7 Kisker

    Project Part B7

    Structure based Drug Design of essentiell enzymes of Mycobacterium tuberculosis and other pathogens

    Prof. Dr. Caroline Kisker

    Rudolf Virchow Center

    Based on estimates from the World Health Organization about a third of the world’s population is infected with Mycobacterium tuberculosis and about 10% of these individuals will develop an active infection. More than two million people die each year due to this disease and more than 8.8 Million new cases are reported annually. Critical issues in the treatment and control of tuberculosis include emergence of multi-drug resistant strains of this organism and the role of this disease as a major opportunistic pathogen in patients with HIV/AIDS. The World Health Organization, the Global Partnership to Stop Tuberculosis and the Millenium Development Project defined new goals for the tuberculosis control programs since the previous strategies were not sufficient to control the disease.

    The focus of my laboratory within the SFB is the analysis of proteins, which are essential for the viability of the organism. We therefore analyze essential enzymes of the fatty acid biosynthesis pathway. Using structure based drug design we aim to develop new inhibitors against drug sensitive and multi-drug resistant strains of Mycobacterium tuberculosis. Based on the broad-spectrum antibiotic Triclosan we have recently developed a series of alkyl-diphenyl ethers that inhibit both drug sensitive and drug-resistant Mycobacterium tuberculosis with a Ki value in the nanomolar range, whereas Triclosan itself only inhibits the organism in the micromolar range. Most importantly the new inhibitor PT70 is a slow-tight-binding inhibitor with a markedly improved residence time.

    We also solved the structure of the essential b-ketoacyl ACP synthase from M. tuberculosis in its apo-form and in complex with the natural product inhibitor thiolactomycin. These structures will now be used to develop new highly specific inhibitors against this enzyme.

    Selected, SFB-relevant Publications

    J. Schiebel, K. Kapilashrami, A. Fekete, G. R. Bommineni, C. M. Schaefer, M. J. Mueller, P. J. Tonge, C. Kisker; Structural Basis for the Recognition of Mycolic Acid Precursors by KasA, a Condensing Enzyme and Drug Target from Mycobacterium Tuberculosis. J Biol Chem 2013. doi:10.1074/jbc.M113.511436

    A. Chang, J. Schiebel, W. Yu, G. R. Bommineni, P. Pan, M. V. Baxter, A. Khanna, C. A. Sotriffer, C. Kisker, P. J. Tonge; Rational optimization of drug-target residence time: insights from inhibitor binding to the Staphylococcus aureus FabI enzyme-product complex. Biochemistry 2013, 52, 4217-4228. doi:10.1021/bi400413c

    J. Schiebel, A. Chang, H. Lu, M. V. Baxter, P. J. Tonge, C. Kisker; Staphylococcus aureus FabI: inhibition, substrate recognition, and potential implications for in vivo essentiality. Structure 2012, 20, 802-813.

    M. W. Hirschbeck, J. Kuper, H. Lu, N. Liu, C. Neckles, S. Shah, S. Wagner, C. A. Sotriffer, P. J. Tonge, C. Kisker; Structure of the Yersinia pestis FabV Enoyl-ACP Reductase and Its Interaction with Two 2-Pyridone Inhibitors. Structure 2012, 20, 89-100.

    B. Schaefer, C. Kisker, C. A. Sotriffer; Molecular dynamics of Mycobacterium tuberculosis KasA: implications for inhibitor and substrate binding and consequences for drug design. J Comput Aided Mol Des 2011, 25, 1053-1069.

    W. Lee, S.R. Luckner, C. Kisker, P.J. Tonge, B. Engels; Elucidation of the Protonation States of the Catalytic Residues in mtKasA: Implications for Inhibitor Design. Biochemistry 2011, 50, 5743-5756.

    S. R. Luckner, N. Liu, C. W. am Ende, P. J. Tonge, C. Kisker; A slow, ight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem 2010, 285, 14330-14337.

    A. Breuning, B. Degel, F. Schulz, C. Buchold, M. Stempka, U. Machon, S. Heppner, C. Gelhaus, M. Leippe, M. Leyh, C. Kisker, J. Rath, A. Stich, J. Gut, P. J. Rosenthal, C. Schmuck, T. Schirmeister; Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease nhibitors with unusual amino acids. J Med Chem 2010, 53, 1951-1963

    C. A. Machutta, G. R. Bommineni, S. R. Luckner, K. Kapilashrami, B. Ruzsicska, C. Simmerling, C. Kisker, P. J. Tonge; Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by hiolactomycin. J Biol Chem 2010, 285, 6161-6169.

    U. Machon, C. Buchold, M. Stempka, T. Schirmeister, C. Gelhaus, M. Leippe, J. Gut, P. J. Rosenthal, C. Kisker, M. Leyh, C. Schmuck; On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences. J Med Chem 2009, 52, 5662-5672.

    S. R. Luckner, C. A. Machutta, P. J. Tonge, C. Kisker; Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin. Structure 2009, 17, 1004-1013.

    H. Lu, K. England, C. am Ende, J. J. Truglio, S. Luckner, B. G. Reddy, N. L. Marlenee, S. E. Knudson, D. L. Knudson, R. A. Bowen, C. Kisker, R. A. Slayden, P. J. Tonge; Slow-onset inhibition of the FabI enoyl reductase from Francisella tularensis: residence time and in vivo activity. ACS Chem Biol 2009, 4, 221-231.

    L. Respicio, P. A. Nair, Q. Huang, B. Anil, S. Tracz, J. J. Truglio, C. Kisker, D. P. Raleigh, I. Ojima, D. L. Knudson, P. J. Tonge, R. A. Slayden; Characterizing septum inhibition in Mycobacterium uberculosis for novel drug discovery. Tuberculosis (Edinb) 2008, 88, 420-429.