Chemical Biology

In their ongoing quest for new therapies against pathogens, scientists are focusing primarily on chemical and biological agents. Discovering new drugs based on such agents, characterising their functionality and optimising their properties are the three main goals of the Department of Chemical Biology (CBIO) at the HZI.

Leader

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. 

Design, Synthesis and Lead Generation of Novel Siderophore Conjugates for the Detection and Treatment of Infections by Gram-Negative Pathogens 

Infections caused by multidrug-resistant Gram-negative bacteria result in significant mortality and morbidity worldwide. In line with this, all pathogens that received a ‘critical’ status by the recently established WHO priority list were drug-resistant Gram-negative species. The reasons for limited success of pharmaceutical research programs in the area of antibiotics have been carefully analyzed: the main hurdle is the limited understanding how to get drugs into Gram-negative bacteria. Thus, there is a strong need for novel, innovative drugs against infections caused by Gram-negative pathogens. There is also a lack of tools to diagnose bacterial infections at deep body sites, e.g. on implant surfaces.

In the project SCAN (Siderophore Conjugates Against gram-Negatives), we apply a rational design approach to establish a targeting conjugate platform that can be used to both diagnose and treat bacterial infections (‘theranostics’ principle). The conjugates are actively transported into bacteria through their iron transport machinery that accepts siderophores as substrates. As this resembles the strategy of ancient Trojan warriors, the approach has been named the ‘Trojan Horse Strategy’. This concept has recently been validated clinically, a first drug (Fetroja) has been approved and is available to patients.

We will design and synthesize artificial siderophores that employ novel central scaffolds and combinations of iron-binding motifs. Those will be coupled with hitherto unexplored effectors: RNA polymerase inhibitors are employed as potent antibiotics, and chemiluminescent probes will be used for imaging. As a linkage between siderophore and antibiotic, cleavable, self-immolative linkers will be constructed. The conjugates will be characterized in cellular assays and in animal infection models. Their translocation and resistance mechanisms will be investigated by genetic and proteomic methods.

The project should yield novel antibiotic lead structures as well as activatable bacterial probes with proven efficacy in vivo to detect and treat infections. Taken together, the afforded antimicrobials and moreover the novel theranostics could be tools that allow for strain-specific, potent treatment and monitoring of bacterial infections, addressing a major medical need expressed by the WHO.

8. Natural product synthesis and semisynthesis

CYSTOBACTAMIDS

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.

SORAPHEN A

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

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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Video

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    Wissenschaftler an der ehemaligen Gesellschaft für Biotechnologische Forschung (GBF), dem heutigen HZI, haben in den 1980er Jahren Epothilon B entdeckt. Dieser Naturstoff stört die Teilung von Krebszellen: Tumore werden durch ihn im Wachstum gebremst, schrumpfen und verschwinden. Das Pharmaunternehmen Bristol-Myers Squibb (BMS) hat jetzt auf der Basis von Epothilon B ein Krebsmedikament auf den US-amerikanischen Markt gebracht. Seine Entwicklung ist so spannend wie ein Krimi...
    Länge: 11:34

  • Molecular Trojan Horses Visualize Infections

    Researchers from the Helmholtz Centre for Infection Research (HZI) and the German Center for Infection Research (DZIF) recently developed molecular probes that utilise the iron transport system of bacteria to transport antibacterial agents into the bacterial cell. These "molecular Trojan horses" can also carry fluorescence markers and thus make infections in smaller animals visible and amenable to treatment. Kevin Ferreira explains here the new developed method in a minute.

  • 1 cure for ALL viruses? 6 new research teams in the challenge by the Federal Agency for Disruptive Innovations [Video in German]

    Six research teams have entered the second phase of the SPRIND Challenge "A Quantum Leap for New Antiviral Agents" with their approach to developing new antiviral agents. Scientists from the Helmholtz Centre for Infection Research are involved in three of the funded projects. YouTuber Jacob Beautemps introduces the teams.

  • How do researchers at the HZI and HIPS develop a new antibiotic?

Audio Podcast

  • 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…
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