In the first two years of our ERC project, we succeeded to make important advances towards a better understanding of Lipid-targeting antibiotics.
The most notable achievements are three publications that deal with the modes of action of antibiotics that target bacterial cell precursors (such as Lipid II) that are embedded in the bacterial plasmamembrane. We could show on the examples of Teixobactin (Shukla et al., Nature 2022, doi: 10.1038/s41586-022-05019-y) Clovibactin (Shukla et al., Cell 2023, doi: 10.1016/j.cell.2023.07.038) and Plectasin (Jekhmane, Derks et al., Nature Microbiology 2024, doi: 10.1016/j.cell.2023.07.038) that these antibiotics target cell wall precursors by assembling into massive supramolecular structures on the membrane-surface. The formation of suprastructures upon target binding is a striking departure from the conventional 1: 1 target paradigm. Thereby, our research opens new avenues for the design of better antibiotics.
On the technological side, our insights were enabled by conceiving a new integrative structural biology approach that combines state-of-the-art solid-state NMR spectroscopy with advanced (confocal and high-speed atomic force) microscopy approaches. Together, these methods enabled to study the action of cell-wall precursor targeting antibiotics across several length-scales (sub-micrometre to angstrom). This was essential to investigate the supramolecular mechanisms of lipid-targeting antibiotics.
Furthermore, we have made important inroads towards a better understanding of daptomycin, and we are confident to make further progress in this direction.
