University of Utrecht
The Mode of Action of Antibiotic-peptide Plectasin in Native Membranes
The rise of multi-drug resistant pathogens urgently calls for the design of powerful novel antibiotics that are robust to resistance development. Ideal templates for such next-generation antibiotics would be peptides that target the highly conserved cell-wall precursor lipid II, also known as the "Achilles' heel of bacteria." Such antibiotics would kill the most refractory pathogens at nanomolecular concentrations. However, due to the challenge of studying small membrane-embedded drug–receptor complexes in native conditions, the structural correlates of the medically relevant binding modes are unknown.
Here we present the physiologically relevant binding mode of the fungal antibiotic Plectasin, a highly promising template for drug design. Previous structural studies presented a model of the plectasin — lipid II complex in micelles, which often poorly mimic physiological membrane conditions and may critically alter the binding mode. We revisit the plectasin — lipid II complex at close-to-physiological conditions using a cutting-edge solid-state NMR approach. Our study reveals drastic differences in the plectasin — lipid II complex in native conditions and unravels, so far unknown, critical lipid II-binding features. Our insights provide a new foundation for the design of next-generation antibiotics using plectasin and other comparable antibiotics as templates.