Project Part A1


Small Molecules against Infectious Diseases

Prof. Dr. Ulrike Holzgrabe

Institute for Pharmacy and Food Technology

Smart and small molecules are aimed to be developed for treatment of tuberculosis, legionellosis, African sleeping  sickness and candidamycosis. Both random chemistry and structure-based drug design will guide the way to innovative active substances.





Quinolone-carboxamides against Trypanosoma brucei brucei:

By serendipity, the high activity of the quinolone-carboxamides against Trypanosoma brucei was detected and optimized. The best compound is shown here. Mode of action: change in the morphology of the mitochondrium; most likely the defect in kinetoplast segregation. This is not identical with ciprofloxacin and thus, not necessarily the topoisomerase.
Development of compounds with high in vivo activity; improvement of water solubility; complete elucidation of the mode of action.
Collaboration partners
: Microbiology: M. Engstler, & N. Jones (TP B8); Pharmaceutics L. Meinel, A. Sakalis (TP Z1)

Bisnaphthalimides against Trypanosoma brucei, Plasmodium falciparum, and resistant Staphylococci aureus

Tertiary bisammonium bisnaphthalimides are known to be cancerostatic. However, the quaternary analogous do not exhibit this cytotoxicity, but are active against tropical protozoa and staphylococci. Of note, the structure-activity relationships of the naphthalamides are different in the different protozoa and Staphylococcus aureaus.
Optimization of the compounds against the various microorganisms. Bisquarternary bistacrine derivatives show a similar activity. Optimization of this series with regard to antiinfective activity and toxicity.
Collaborations partners
: Microbiology: K. Ohlsen (TP B5), H. Moll & U. Schurigt (TP B8), A. Stich (TP Z1), G. Pradel (Aachen)

KasA inhibitors against Mycobacterium tubercolusis

The structures of the human and bacterial enzymes building fatty acids are already elucidated. This holds true inter alia for the elongation-condensation enzyme FabB of E. coli. The corresponding enzyme KasA was isolated from mycobacteria and structurally characterized in presence of the thiolactomycin inhibitor. Virtual screening gave suggestions for inhibitors which were synthesized and biologically evaluated by means of a fluorescence assay. Some compounds exhibiting good KasA inhibitory activity were identified which are in part active against mycobacterium tuberculosis.
Development of an enzyme assay which specifically measures the inhibition of KasA; crystal structure of KasA complexed with a newly synthesized inhibitor.
Collaborations partners
: C. Kisker (TP B7), C. Sotriffer (TP C7), P. Tonge (Stony Brook, NY, USA).

Search for antileishmanial natural products in Valeriana wallichii:

The extract from the plant collected in India was found to have substantial antileishmanial activity which might be due to an antiprotease activity.
: Isolation of the most active compound in the extract and elucidation of the mode of action
Collaborations partner
s: H. Moll & U. Schurigt (TP B3); T. Schirmeister (TP A4), B. Hazra (Kolkatta, India)

Inhibitors of Macrophage infectivity potentiator (Mip) from Legionella pneumophila and Burkholderia pseudomallei

The Macrophage infectivity potentiator (Mip) protein is an extracellullar major virulence factor produced e. g. by Legionella pneumophila and contributes to the bacterial dissemination within the lung tissue and the spread of Legionella to the spleen. Mip exhibits a peptidyl prolyl cis-trans isomerase activity (PPIase) which is targeted by pipecolic acid derivatives being partially active against Burkholderia pseudomallei, too.
Optimization of the anti-PPIase-activity and antiinfective activity against Burkholderia pseudomallei; investigation of the mode of action of the PPIase-Mip-inhibition against Legionella
Collaboration partners
: Legionella: PPIase-Assay: M. Weiwad, A. Thiele, MPI Proteinfaltung, Halle; NMR spectroscopy: P. Rösch, K. Schweimer, Department Biopolymers, Bayreuth; C. Sotriffer (TP C7); Infection assay: M. Steinert, Mikrobiologie, Braunschweig (former TP B1); Burkholderia Biology: I. H. Norville; (Exeter, Salisbury, UK); Protein crystallography and NMR: R. Stacy, M. Sarkar-Tyson, D. Lorimer (EmeraldBio, Seattly, USA)


Selected, SFB-relevant Publications

D. W. Begley, D. Fox, 3rd, D. Jenner, C. Juli, P. G. Pierce, J. Abendroth, M. Muruthi, K. Safford, V. Anderson, K. Atkins, S. R. Barnes, S. O. Moen, A. C. Raymond, R. Stacy, P. J. Myler, B. L. Staker, N. J. Harmer, I. H. Norville, U. Holzgrabe, M. Sarkar-Tyson, T. E. Edwards, D. D. Lorimer; A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrob Agents Chemother 2014, 58, 1458-1467. doi:10.1128/AAC.01875-13

J. Glaser, M. Schultheis, S. Hazra, B. Hazra, H. Moll, U. Schurigt, U. Holzgrabe; Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester. Molecules 2014, 19, 1394-1410. doi:10.3390/molecules19021394

A. Stich, A. Ponte-Sucre, U. Holzgrabe; Do we need new drugs against human African trypanosomiasis? Lancet Inf Diseases 2013, 13, 733-734. doi:10.1016/S1473-3099(13)70191-9

G. Hiltensperger, N. G. Jones, S. Niedermeier, A. Stich, M. Kaiser, J. Jung, S. Puhl, A. Damme, H. Braunschweig, L. Meinel, M. Engstler, U. Holzgrabe; Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei. J Med Chem 2012, 55, 2538-2548.

M. Tischer, G. Pradel, K. Ohlsen, U. Holzgrabe; Quaternary ammonium salts and their antimicrobial potential: targets or nonspecific interactions? ChemMedChem (invited review) 2012, 7, 22-31.

A. Cecil, C. Rikanovic, K. Ohlsen, C. Liang, J. Bernhardt, T. A. Oelschlaeger, T. Gulder, G. Bringmann, U. Holzgrabe, M. Unger, T. Dandekar; Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells. Genome Biol 2011, 12, R24.

E. Kugelmann, C. R. Albert, G. Bringmann, U. Holzgrabe; Fenton's oxidation: a tool for the investigation of potential drug metabolites. J Pharm Biomed Anal 2011, 54, 1047-1058.

C. Juli, M. Sippel, J. Jäger, A. Thiele, M. Weiwad, K. Schweimer, P. Rösch, M. Steinert, C. A. Sotriffer, U. Holzgrabe; Pipecolic acid derivatives as small-molecule inhibitors of the Legionella MIP protein. J Med Chem 2011, 54, 277-283.

S. Ghosh, S. Debnath, S. Hazra, A. Hartung, K. Thomale, M. Schultheis, P. Kapkova, U. Schurigt, H. Moll, U. Holzgrabe, B. Hazra; Valeriana wallichii root extracts and fractions with activity against Leishmania spp. Parasitol Res 2011, 108, 861-871.

T. M. Menzel, M. Tischer, P. Francois, J. Nickel, J. Schrenzel, H. Bruhn, A. Albrecht, L. Lehmann, U. Holzgrabe, K. Ohlsen; Mode-of-action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus. Antimicrob Agents Chemother 2011, 55, 311-320.

 M. Tischer, L. Sologub, G. Pradel, U. Holzgrabe; The Bisnaphthalimides as New Active Lead Compounds against Plasmodium falciparum. Bioorg Med Chem 2010, 18, 2998-3003 (with cover picture).

B. Waibel, C. Albert, U. Holzgrabe; Evaluation of the extent of protein binding by means of NMR diffusion and relaxation experiments, and automated continuous ultrafiltration. Eur J Pharm Sci 2009, 37, 191-197.

H. Gahaly, C. Kriete, S. Sahin, A. Pflöger, U. Holzgrabe, B.J. Zünkler, I. Rustenbeck; The insulinotropic effect of fluoroquinolones, Biochem Pharmacol 2009, 77, 1040-1052.

A. Ponte-Sucre, T. Gulder, A. Wegehaupt, C. Albert, M. Schultheis, U. Holzgrabe, G. Bringmann, H. Moll; Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts. J Med Chem 2009, 52, 626-636.

F. Diwischek, J. Morschhäuser, U. Holzgrabe; Cerulenin analogues as inhibitors of efflux pump in drug-resistant Candida albicans. Arch Pharm Chem Life Sci 2009, 342, 150-164.

E. Kugelmann, U. Holzgrabe; Generation of small-compound libraries via re-combinatorial chemistry by Fenton´s reagent. Arkivoc 2008, XI, 247-255.

T. Goebel, D. Ulmer, H. Projahn, A. Ponte-Sucre, M. Saeftel, A. Hoerauf, A. Kaiser, I. Hauber, J. Hauber, U. Holzgrabe; In search of novel agents for therapy of tropical diseases and Human Immunodeficiency Virus. J Med Chem 2008, 51, 238-250.

V. Hoerr, W. Ziebuhr, S. Kozitskaya, E. Katzowitsch, U. Holzgrabe; Laser-Induced Fluorescence-Capillary Electrophoresis and Fluorescence Microplate Reader Measurement: Two Methods to Quantify the Effect of Antibiotics. Anal Chem 2007, 79, 7510-7518, reported by D.L. Shenkenberg in Biophotonics International, Dec. 2007, 57-58.

U. Neugebauer, U. Schmid, K. Baumann, U. Holzgrabe, J. Popp; Towards an understanding of the mode of action of fluoroquinolone drugs. Proceedings of the International Society for Optical Engineering Band 2007, 6633, Biophotonics 2007: Optics in Life Science, J. Popp; G. von Bally (Herausgeber), Progress in biomedical optics and imaging, 66331W, DOI: 10.1117/12.728137

U. Neugebauer, U. Schmid, K. Baumann, W. Ziebuhr, S. Koziskaya, U. Holzgrabe, M. Schmitt, J. Popp; The influence of fluoroquinolone drugs on the bacterial growth of S. epidermidis utilizing the unique potential of vibrational spectroscopy. J Phys Chem A 2007, 111, 2898-2906.

B. Waibel, U. Holzgrabe; 1H and 19F NMR relaxation studies of fleroxacin with Micrococcus luteus. J Pharm Biomed Anal 2007, 43, 1595-1601.

M. Muth, V. Hoerr, A. Stich, U. Holzgrabe; Antitrypanosomal activity of quaternary naphthalimide derivatives. Bioorg Med Chem Lett 2007, 17, 1590-1593.


Reviews and professional qualification

C. M. Topf, J. Schiebel, C. Kisker, U. Holzgrabe; Die Fettsäuresynthese als Zielstruktur von alten und neuen antimykobateriellen Wirkstoffen. Pharm Unserer Zeit 2012, 41, 64-70.

U. Holzgrabe, M. Abele-Horn; MRSA - Entstehung, Verbreitung, Behandlung und Prävention. Med Mo Pharm 2012, in press.

U. Holzgrabe, M. Schlitzer, A. Stich (Herausgeber) Tropenerkrankungen 2, Themenheft der Pharm i u Z , 2010, Heft 1

U. Holzgrabe, M. Schlitzer, A. Stich (Herausgeber) Tropenerkrankungen 1, Themenheft der Pharm i u Z, 2009 Heft 6

U. Holzgrabe; Problem Arzneimittelfälschungen in Afrika und Südostasien. Pharm i u Z, 2009, 38, 560-562.

U. Holzgrabe; Meropenem-Clavulanate – a new strategy for the treatment of tuberculosis? ChemMedChem 2009, 4, 1051-1053.

U. Holzgrabe; J. Schmitz, Neue Antibiotika – den Vorsprung gegenüber resistenten Bakterien wahren? Pharm Ztg 2009, 154, 4780-4787.

U. Holzgrabe; The light at the end of the tunnel? A hopeful beginning for a malaria vaccine Int Pharmacy J 2009, 24, 31-34.