Novel extracellular-targeted antibiotics
Bacteria that are resistant to multiple drugs are becoming a serious threat for public health. In consequence, the need for innovative antibiotics has sharply increased. The Department of Chemical Biology (CBIO) addresses this need by the design, synthesis and optimization of novel targeted antibiotics. Following a so-called Trojan horse strategy, a bio-ligand or targeting moiety such as a sugar-residue or an iron-complex is recognized by bacterial transporters and actively translocated into the cell. The targeting moiety is covalently linked to an antibiotic that kills the bacterium following internalization.
Furthermore, new antibacterial natural products and natural product-derived compounds are investigated mechanistically and chemically optimized to treat infections and kill multi-drug resistant pathogens.
Sugar conjugates – exploring active transport mechanisms into Gram-negative bacteria.
Bacteria internalize maltodextrin units through dedicated maltodextrin transporter systems like E. coli’s LamB. In our approach, oligomers of maltose are functionalized at various positions and used as transporters for antibiotics into the bacterial cell. Microbiological, imaging-based, and mass spectrometry-based assays to detect their translocation are available in the department.
Siderophores as targeting moieties
Bacteria satisfy their iron demand through an active uptake of self-made and/or foreign siderophore molecules. We utilize these siderophore transporters for antibiotic uptake by coupling siderophore motifs to antibiotics using a DOTAM/metal scaffold. Conjugation of dyes but also drugs against Gram-negative bacteria is an opportunity to improve the detection and the treatment of bacterial infection.
In additional projects, we search for and optimize artificial siderophore mimics, and systematically investigate the conditions of cargo uptake. Microbiological, imaging-based, and mass spectrometry-based assays to measure the translocation efficiency are available in the department.
- Ferreira, K., Hu, H.Y., Fetz, V., Prochnow, H., Rais, B., Müller, P.P. & Brönstrup, M. (2017) Multivalent Siderophore–DOTAM Conjugates as Theranostics for Imaging and Treatment of Bacterial Infections. Angewandte Chemie International Edition, 56, 8272-8276.
Affinity based protein profiling with disorazole A1
Disorazole A1 is a metabolite produced by myxobacteria (Sorangium cellulosam strain So Ce 12) that exhibits remarkable cytostatic activity in eukaryotic cells in the picomolar range (Jansen et al., Liebigs Ann. Chem. 1994, 759-73). Mode of action studies have shown that the compound inhibits tubulin polymerization. Our own data demonstrate that the compound affects additional intracellular pathways that cannot be explained by tubulin binding alone. We have therefore synthesized affinity probes of disorazole A1 that can be used for the identification of additional cellular target by affinity–based proteomics.
8. Natural product synthesis and semisynthesis
Cystobactamids, new natural products isolated from myxobacteria (Baumann et al., Angew. Chem. Int. Ed. 2014, 53, 14605-9), show potent biological activity against a panel of Gram-positive and, most notably, Gram-negative bacteria like E. coli. Cystobactamids are aromatic oligopeptides with one aliphatic amino acid that can be regarded as a spacer between the aromatic rings. Cystobactamids are topoisomerase inhibitors, interacting with GyrA and DNA in a yet undefined phase of the catalytic cycle. Based on these promising properties, a multidisciplinary research project involving clarification of the mechanism of action, total synthesis of the natural products and a medicinal chemistry program has been initiated, involving partners at HZI, HIPS and LUH.
We have established three different routes by total synthesis. These routes enabled a medicinal chemistry program of these novel natural products that helped establishing structure-activity relationships (SAR). This led to the identification of analogs with superior potency compared to the natural compounds. We also explore the cystobactamide scaffold as a chemical biology tool in form of photo switches or carriers of cargo.
- Hüttel, S., Testolin, G., Herrmann, J., Planke, T., Gille, F., Moreno, M., Stadler, M., Brönstrup, M., Kirschning, A. & Müller, R. (2017) Discovery and total synthesis of natural cystobactamid derivatives with superior activity against Gram-negative pathogens. Angewandte Chemie International Edition, 56, in press, DOI: 10.1002/anie.201705913.
Semisynthesis of new derivatives of soraphen A for the exploration of structure-activity relationships
Soraphen A has been isolated from the myxobacterium Sorangium cellulosum. As a highly potent inhibitor of acetyl-CoA carboxylase (ACC), soraphens can be applied to interfere with lipogenensis and fatty acid oxidation. This effect can be utilized in several indications, e.g. in autoimmune diseases, or to treat a broad spectrum of viral infections. We derivatize soraphen A at various positions with the aim to enhance the metabolic stability and to increase its solubility.
- The myxobacterial metabolite Soraphen A inhibits HIV-1 by reducing virus production and altering virion composition. Fleta-Soriano E, Smutná K, Martinez JP, Lorca Oró C, Sadiq SK, Mirambeau G, Lopez-Iglesias C, Bosch M, Pol A, Brönstrup M, Diez J, Meyerhans A. Antimicrobial Agents and Chemotherapy (2017), pii: AAC.00739-17. doi: 10.1128/AAC.00739-17.
- Soraphen A: a broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity. Koutsoudakis, George; Romero-Brey, Inés; Berger, Carola; Pérez-Vilaró, Gemma; M. Perin, Paula; Vondran, Florian W.R.; Kalesse, Markus; Harmrolfs, Kirsten; Müller, Rolf; Martinez, Javier P.; Pietschmann, Thomas; Bartenschlager, Ralf; Bronstrup, Mark; Meyerhans, Andreas; Diez, Juana. Journal of Hepatology (2015), 63(4), 813-21.
Chelocardin is a potent broad spectrum antibiotic produced by Nocardea sulphurea, which has a structural resemblance with tetracycline. Due to its broad-spectrum antibiotic activity, particularly against ‘ESKAPE’ pathogens, the genetically engineered analog amidochelocardin (Lesnik et al., Angew. Chem. Int. Ed., 2015, 54, 3937-40) is considered an ideal candidate for anti-infective drug development. However, some gaps in the amidochelocardin antibiotic spectrum, e.g. against Pseudomonas strains, remain to be closed by chemical modifications, which are currently explored by our group.
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- Kleine Moleküle ganz groß – Mit Naturstoffen gegen Hepatitis CMit weltweit 130 Millionen Infizierten ist Hepatitis C eine der häufigsten Infektionskrankheiten. Die Therapien, die es derzeit gibt, sind langwierig, haben starke Nebenwirkungen und helfen nicht jedem Patienten. Florenz Sasse vom Braunschweiger Helmholtz-Zentrum für Infektionsforschung und Thomas Pietschmann vom TWINCORE in Hannover suchen gemeinsam nach neuen Wirkstoffen gegen das Hepatitis C-Virus. Hören Sie hier von ihren ersten Treffern und folgen Sie Florenz Sasse zu einer Bibliothek der anderen Art…