SFB 630: Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases
Biology
Medicine
Final Report Abstract
The goal of the Collaborative Research Center has been to support the identification and development of novel anti-infectives in an academic environment. Even though in the meantime the topic received much attention in politics worldwide, the overall situation does not appear much different today. In low-income countries, infections are still the leading cause of death. For a number of poverty-associated tropical infections (“neglected diseases”), the WHO roadmap for controlling, elimination or eradication of 2012 identified preventive chemotherapy as a key strategy, but there is still a lack of suitable and affordable drugs. Moreover, resistances against the major classes of antimicrobials are fast emerging and widespread in developed countries, too. In 2014, the WHO stated that a post-antibiotic era is a very real possibility for the 21st century. Hence, the search for novel anti-infectives is still as urgent today as in the beginning of the Collaborative Research Center and still justifies the involvement of academic science. We focused on the research for drugs against trypanosomes, Leishmania, Candida, mycobacteria, Legionella, staphylococci including MRSA, chlamydia and Neisseria. The extraordinary interdisciplinary cooperation of microbiologists, pharmacists, chemists, physicists, physicians, and computational chemists and biologists is evidenced by more than 460 peer-reviewed scientific publications. Here, some representative highlights will be given only: 1. Basic virulence and resistance mechanisms of pathogens have been analyzed in Candida albicans, for instance. In this fungus, resistance is mainly provoked by the expression of efflux pumps that is regulated by a subtle interplay of different transcription factors. Knowing their stimulation, activation, and impact on Candida fitness is a major premise to overcome antifungal resistance. 2. A major mechanism of African trypanosomes to invade the human immune system is antigenic variation. We could educe a model that mechanistically links this process to stage development of the parasite and hence points to a novel point of attack against African sleeping sickness. 3. Novel in-vivo imaging techniques were combined that allow for the first time the analysis of bacterial infection dynamics and kinetics on both sides, the pathogen development as well as the cellular immune response of the host in parallel and in real time. 4. We did not only investigate the mode of action of anti-infectives in cellular pathways like autophagy and apoptosis, but also down to the atomic level for their interaction with protein targets. The combined efforts of experts in structural biology, theoretical and computational chemistry, organic synthesis, and biochemistry lead to the development of a novel strategy for the tailor-made design of covalent protein ligands. From known structural interactions of irreversible protease inhibitors, corresponding covalent reversible inhibitors were designed by quantum mechanical calculations and docking studies. These inhibitors display favorable kinetic parameters in vitro, are highly active against trypanosomes and are - as anticipated - substantially less cytotoxic. 5. Regarding chemistry and pharmacy, novel routes for synthesis, structural characterization, and galenic formulation of anti-infectives were generated. For selected candidate molecules of quinolonamides, naphthylisoquinoline derivatives, pipecolic acid esters, and cinnamic acid derivatives, the efficacy in animal models for African trypanomiasis, malaria, melioidosis, or leishmaniasis has been evidenced – a key step for the takeover by product development organizations like “Drugs for neglected diseases initiative” or by the pharmaceutical industry.
Publications
- 3,3-Dimethyl-8- oxoisochinoline, Verfahren zu ihrer Herstellung, sie enthaltende pharmazeutische Zusammensetzungen und deren Verwendung. Deutsches Patent DE 103 03 254 B3 (23.09.2004)
G. Bringmann, C. Rummey, S. Neumann, R. Brun, A. Stich, V. Hörr, W.E.G. Müller
- Biofilm-hemmende Wirkung sowie antiinfektive Aktivität N,C- verknüpfter Arylisochinoline, deren pharmazeutische Zusammensetzung und deren Verwendung. Deutsches Patent DE 10 2006 046 922 B3 (15.11.2007)
G. Bringmann, T. Gulder, U. Hentschel, F. Meyer, H. Moll, J. Morschhäuser, A. Ponte-Sucre, A. Stich, R. Brun, W.E.G. Müller, V. Mudogo
- Direct and label-free detection of solidphase-bound compounds by using surface-enhanced Raman scattering microspectroscopy. Angew Chem Int Ed Engl 2007, 46, 4786-4789
C. Schmuck, P. Wich, B. Küstner, W. Kiefer, S. Schlücker
(See online at https://dx.doi.org/10.1002/anie.200605190) - The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog 2007, 3, e164
J. Morschhäuser, K. S. Barker, T. T. Liu, B. W. J. Bla, R. Homayouni, P. D. Rogers
(See online at https://dx.doi.org/10.1371/journal.ppat.0030164) - Antiinfective and antitumoral compounds isolated from tropical lianas. Europäische Patentanmeldung EP 2093 207 A8 (16.05.2008); International Patent Application PCT/EP2009/000855 (06.02.2009)
G. Bringmann, S. Rüdenauer, R. Brun, A. Irmer, R. Bargou, M. Chatterjee, A. Voskobojnik
- 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
U. Machon, C. Büchold, M. Stempka, T. Schirmeister, C. Gelhaus, M. Leippe, J. Gut, P. J. Rosenthal, C. Kisker, M. Leyh, C. Schmuck
(See online at https://dx.doi.org/10.1021/jm900629w) - Quantitative CARS microscopic detection of analytes and their isotopomers in a two-channel microfluidic chip. Small 2009, 5, 2816-2818
G. Bergner, S. Chatzipapadopoulos, D. Akimov, B. Dietzek, D. Malsch, T. Henkel, S. Schlücker, J. Popp
(See online at https://dx.doi.org/10.1002/smll.200900807) - Genkonversionskonstrukt und Verfahren zur Vererbung von Genmobilität sowie Verwendung des Konstruktes. DE102006021516 (25.03.2010)
T. Löwe, R. Gross, T. Dandekar
- Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids. J Med Chem 2010, 53, 1951-1963
A. Breuning, B. Degel, F. Schulz, C. Büchold, 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
(See online at https://dx.doi.org/10.1021/jm900946n) - Total synthesis of the N,C-coupled naphthylisoquinoline alkaloids ancistrocladinium A and B and related analogues. J Am Chem Soc 2010, 132, 1151-1158
G. Bringmann, T. Gulder, B. Hertlein, Y. Hemberger, F. Meyer
(See online at https://dx.doi.org/10.1021/ja9097687) - Development of antitrypanosomal and antiplasmodial nonpeptidic cysteine protease inhibitors based on N-protected-guanidino-furan and -pyrrole building blocks. ChemMedChem 2011, 6, 1581-1586
S. Langolf, U. Machon, M. Ehlers, W. Sicking, T. Schirmeister, C. Buchhold, C. Gelhaus, P. J. Rosenthal, C. Schmuck
(See online at https://dx.doi.org/10.1002/cmdc.201100189) - Functional dissection of a Candida albicans zinc cluster transcription factor, the multidrug resistance regulator Mrr1. Eukaryot Cell 2011, 10, 1110- 1121
S. Schubert, C. Popp, P. D. Rogers, J. Morschhäuser
(See online at https://dx.doi.org/10.1128/EC.05100-11) - Mode-of-action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus. Antimicrob Agents Chemother 2011, 55, 311-320
T. M. Menzel, M. Tischer, P. Francois, J. Nickel, J. Schrenzel, H. Bruhn, A. Albrecht, L. Lehmann, U. Holzgrabe, K. Ohlsen
(See online at https://dx.doi.org/10.1128/AAC.00586-10) - 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
A. Cecil, C. Rikanovic, K. Ohlsen, C. Liang, J. Bernhardt, T. A. Oelschlaeger, T. Gulder, G. Bringmann, U. Holzgrabe, M. Unger, T. Dandekar
(See online at https://dx.doi.org/10.1186/gb-2011-12-3-r24) - New cis-configured aziridine-2- carboxylates as aspartic acid protease inhibitors. ChemMedChem 2011, 6, 141-152
C. Büchold, Y. Hemberger, C. Heindl, A. Welker, B. Degel, T. Pfeuffer, P. Staib, S. Schneider, P. J. Rosenthal, J. Gut, J. Morschhäuser, G. Bringmann, T. Schirmeister
(See online at https://dx.doi.org/10.1002/cmdc.201000370) - Pipecolic acid derivatives as small-molecule inhibitors of the Legionella MIP protein. J Med Chem 2011, 54, 277-283
C. Juli, M. Sippel, J. Jager, A. Thiele, M. Weiwad, K. Schweimer, P. Rosch, M. Steinert, C. A. Sotriffer, U. Holzgrabe
(See online at https://dx.doi.org/10.1021/jm101156y) - Quantitative detection of C-deuterated drugs by CARS microscopy and Raman microspectroscopy. Analyst 2011, 136, 3686-3693
G. Bergner, C. R. Albert, M. Schiller, G. Bringmann, T. Schirmeister, B. Dietzek, S. Niebling, S. Schlücker, J. Popp
(See online at https://dx.doi.org/10.1039/c0an00956c) - Quantitative, label-free and site-specific monitoring of molecular recognition: a multivariate resonance Raman approach. Chem Commun (Camb) 2011, 47, 568-570
S. Niebling, H. Y. Kuchelmeister, C. Schmuck, S. Schlücker
(See online at https://dx.doi.org/10.1039/c0cc02052d) - Highly selective antiplasmodial naphthylisoquinoline alkaloids from Ancistrocladus tectorius. Phytochemistry 2012
G. Bringmann, G. Zhang, T. Ölschläger, A. Stich, J. Wu, M. Chatterjee, R. Brun
(See online at https://doi.org/10.1016/j.phytochem.2012.02.017) - Quaternary ammonium salts and their antimicrobial potential: targets or nonspecific interactions? ChemMedChem 2012, 7, 22-31
M. Tischer, G. Pradel, K. Ohlsen, U. Holzgrabe
(See online at https://doi.org/10.1002/cmdc.201100404) - Staphylococcus aureus FabI: inhibition, substrate recognition, and potential implications for in vivo essentiality. Structure 2012, 20, 802-813
J. Schiebel, A. Chang, H. Lu, M. V. Baxter, P. J. Tonge, C. Kisker
(See online at https://doi.org/10.1016/j.str.2012.03.013) - Structure of the Yersinia pestis FabV Enoyl-ACP Reductase and Its Interaction with Two 2-Pyridone Inhibitors. Structure 2012, 20, 89-100
M. W. Hirschbeck, J. Küper, H. Lu, N. Liu, C. Neckles, S. Shah, S. Wagner, C. A. Sotriffer, P. J. Tonge, C. Kisker
(See online at https://doi.org/10.1016/j.str.2011.07.019) - Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei. J Med Chem 2012, 55, 2538-2548
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
(See online at https://doi.org/10.1021/jm101439s) - The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans. Mol Microbiol 2012, 86, 539-556
C. Sasse, N. Dunkel, T. Schäfer, S. Schneider, F. Dierolf, K. Ohlsen, J. Morschhäuser
(See online at https://doi.org/10.1111/j.1365-2958.2012.08210.x) - A novel Leishmania major amastigote assay in 96-well format for rapid drug screening and its use for discovery and evaluation of a new class of leishmanicidal quinolinium salts. Antimicrob Agents Chemother 2013, 57, 3003-3011
G. Bringmann, K. Thomale, S. Bischof, C. Schneider, M. Schultheis, T. Schwarz, H. Moll, U. Schurigt
(See online at https://doi.org/10.1128/AAC.02201-12) - A primaquine-chloroquine hybrid with dual activity against Plasmodium liver and blood stages. Int J Med Microbiol 2013
M. Lödige, M. D. Lewis, E. S. Paulsen, H. L. Esch, G. Pradel, L. Lehmann, R. Brun, G. Bringmann, A. K. Mueller
(See online at https://doi.org/10.1016/j.ijmm.2013.07.005) - Do we need new drugs against human African trypanosomiasis? Lancet Inf Diseases 2013, 13, 733-734
A. Stich, A. Ponte-Sucre, U. Holzgrabe
(See online at https://dx.doi.org/10.1016/S1473-3099(13)70191-9) - Jozimine A2: the first dimeric Dioncophyllaceae-type naphthylisoquinoline alkaloid, with three chiral axes and high antiplasmodial activity. Chemistry 2013, 19, 916-923
G. Bringmann, G. Zhang, T. Buttner, G. Bauckmann, T. Kupfer, H. Braunschweig, R. Brun, V. Mudogo
(See online at https://doi.org/10.1002/chem.201202755) - MycPermCheck: the Mycobacterium tuberculosis permeability prediction tool for small molecules. Bioinformatics 2013, 29, 62-68
B. Merget, D. Zilian, T. Müller, C. A. Sotriffer
(See online at https://doi.org/10.1093/bioinformatics/bts641) - Optimization of triazine nitriles as rhodesain inhibitors: structure-activity relationships, bioisosteric imidazopyridine nitriles, and X-ray crystal structure analysis with human cathepsin L. ChemMedChem 2013, 8, 967-975
V. Ehmke, E. Winkler, D. W. Banner, W. Haap, W. B. Schweizer, M. Rottmann, M. Kaiser, C. Freymond, T. Schirmeister, F. Diederich
(See online at https://doi.org/10.1002/cmdc.201300112) - Pilus phase variation switches gonococcal adherence to invasion by caveolin-1-dependent host cell signaling. PLoS Pathog 2013, 9, e1003373
M. Faulstich, J. P. Böttcher, T. F. Meyer, M. Fraunholz, T. Rudel
(See online at https://doi.org/10.1371/journal.ppat.1003373) - Rational optimization of drug-target residence time: insights from inhibitor binding to the Staphylococcus aureus FabI enzyme-product complex. Biochemistry 2013, 52, 4217-4228
A. Chang, J. Schiebel, W. Yu, G. R. Bommineni, P. Pan, M. V. Baxter, A. Khanna, C. A. Sotriffer, C. Kisker, P. J. Tonge
(See online at https://doi.org/10.1021/bi400413c) - Structure and function of the PorB porin from disseminating Neisseria gonorrhoeae. Biochem J 2013, 449, 631-642
K. Zeth, V. Kozjak-Pavlovic, M. Faulstich, M. Fraunholz, R. Hurwitz, O. Kepp, T. Rudel
(See online at https://doi.org/10.1042/BJ20121025) - Bioluminescence and 19F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models. Antimicrob Agents Chemother 2014, 58, 1630-1638
T. Hertlein, V. Sturm, U. Lorenz, K. Sumathy, P. Jakob, K. Ohlsen
(See online at https://doi.org/10.1128/AAC.01422-13) - Cathepsin B in antigen-presenting cells controls mediators of the Th1 immune response during Leishmania major infection. PLoS Negl Trop Dis 2014, 8, e3194
I. J. Gonzalez-Leal, B. Roger, A. Schwarz, T. Schirmeister, T. Reinheckel, M. B. Lutz, H. Moll
(See online at https://doi.org/10.1371/journal.pntd.0003194) - Compounds and markers for surface-enhanced Raman scattering. PCT Int. Appl. 2009; US2010284917 (07.10.2014)
B. Kuestner, S. Schluecker, C. Schmuck
- Dereplication strategies for targeted isolation of new antitrypanosomal actinosporins A and B from a marine sponge associated-Actinokineospora sp. EG49. Mar Drugs 2014, 12, 1220-1244
U. R. Abdelmohsen, C. Cheng, C. Viegelmann, T. Zhang, T. Grkovic, S. Ahmed, R. J. Quinn, U. Hentschel, R. Edrada-Ebel
(See online at https://doi.org/10.3390/md12031220) - Evidence for substrate binding-induced zwitterion formation in the catalytic Cys-His dyad of the SARS-CoV main protease. Biochemistry 2014, 53, 5930-5946
A. Paasche, A. Zipper, S. Schäfer, J. Ziebuhr, T. Schirmeister, B. Engels
(See online at https://doi.org/10.1021/bi400604t) - Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei. Elife 2014, 3, e02324
C. Batram, N. G. Jones, C. J. Janzen, S. M. Markert, M. Engstler
(See online at https://doi.org/10.7554/eLife.02324) - The Protonation State of Catalytic Residues in the Resting State of KasA Revisited: Detailed Mechanism for the Activation of KasA by Its Own Substrate. Biochemistry 2014, 53, 919- 931
W. Lee, B. Engels
(See online at https://doi.org/10.1021/bi401308j) - Anti-trypanosomal activities and structural chemical properties of selected compound classes. Parasitol Res 2015, 114, 501-512
A. Ponte-Sucre, H. Bruhn, T. Schirmeister, A. Cecil, C. R. Albert, C. Buechold, M. Tischer, S. Schlesinger, T. Goebel, A. Fuss, D. Mathein, B. Merget, C. A. Sotriffer, A. Stich, G. Krohne, M. Engstler, G. Bringmann, U. Holzgrabe
(See online at https://doi.org/10.1007/s00436-014-4210-4) - Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210. Parasit Vectors 2015, 8, 404
B. Frank, A. Marcu, A. L. de Oliveira Almeida Petersen, H. Weber, C. Stigloher, J. C. Mottram, C. J. Scholz, U. Schurigt
(See online at https://doi.org/10.1186/s13071-015-0974-3) - Elicitation of secondary metabolism in actinomycetes. Biotechnol Adv 2015
U. R. Abdelmohsen, T. Grkovic, S. Balasubramanian, M. S. Kamel, R. J. Quinn, U. Hentschel
(See online at https://doi.org/10.1016/j.biotechadv.2015.06.003) - FadA5 a thiolase from Mycobacterium tuberculosis: a steroid-binding pocket reveals the potential for drug development against tuberculosis. Structure 2015, 23, 21-33
C. M. Schaefer, R. Lu, N. M. Nesbitt, J. Schiebel, N. S. Sampson, C. Kisker
(See online at https://doi.org/10.1016/j.str.2014.10.010) - Inhibitory activities of the marine streptomycete-derived compound SF2446A2 against Chlamydia trachomatis and Schistosoma mansoni. J Antibiot (Tokyo) 2015
A. Reimer, A. Blohm, T. Quack, C. G. Grevelding, V. Kozjak-Pavlovic, T. Rudel, U. Hentschel, U. R. Abdelmohsen
(See online at https://doi.org/10.1038/ja.2015.54) - Vinyl sulfone building blocks in covalently reversible reactions with thiols. New Journal of Chemistry 2015, 39, 5841-5853
T. H. Schneider, M. Rieger, K. Ansorg, A. N. Sobolev, T. Schirmeister, B. Engels
(See online at https://doi.org/10.1039/c5nj00368g)
