Chemical Biology

Our Research

© HZI / CBIO

Our drug discovery program employs state-of-the-art chemical strategies to tackle infectious diseases. A great challenge in the development of new antibiotics is finding a way to penetrate the double membranes of Gram-negative bacteria, the group of bacteria that also contain many drug-resistant variants. We conduct structure–activity relationship (SAR) studies and medicinal chemistry campaigns on both natural products and synthetic compounds, producing potent novel derivatives with new modes of action, and good efficacy in vivo. Moreover, we have refined the “Trojan Horse” strategy, whereby we exploit the need for iron of bacteria to gain access into them using molecules called “siderophores” (Greek for “iron carriers”). By conjugating these siderophores to antibiotics, the drugs can be directly transported into bacteria, like the Trojan Horse carrying soldiers into Troy. This conjugation strategy is also expanded to include the development of diagnostic tools for infection imaging. Additionally, to develop new antiviral agents, we are also exploring the use of new drug modalities, e.g. PROTACs, which degrade the target protein, as opposed to inhibiting it in the way that traditional drugs do.

For all newly synthesized compounds, a profound understanding of their mode of action is a prerequisite to enable a rational design. We employ metabolomics to investigate cellular effects of antibacterial compounds. We pioneered a mass-spectrometry-based method to measure the uptake of compounds into Gram-negative bacteria. Moreover, we apply mass spectrometry-based chemoproteomics to aid target discovery. Our profiling activities also involve a suite of highly automated biological assays and the design and production of peptide arrays to characterise antibacterial and antiviral compounds. Peptide arrays are produced inhouse for a high resolution epitope mapping of antibody mixtures.