Chemische Biologie

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.

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.

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