Abstract
The alarming rise of antimicrobial resistance requires antibiotics with unexploited mechanisms. Ideal templates could be antibiotics that target the peptidoglycan precursor lipid II, known as the bacterial Achilles heel, at an irreplaceable pyrophosphate group. Such antibiotics would kill multidrug-resistant pathogens at nanomolecular concentrations without causing antimicrobial resistance. However, due to the challenge of studying small membrane-embedded drug–receptor complexes in native conditions, the structural correlates of the pharmaceutically relevant binding modes are unknown. Here, using advanced highly sensitive solid-state NMR setups, we present a high-resolution approach to study lipid II-binding antibiotics directly in cell membranes. On the example of nisin, the preeminent lantibiotic, we show that the native antibiotic-binding mode strongly differs from previously published structures, and we demonstrate that functional hotspots correspond to plastic drug domains that are critical for the cellular adaptability of nisin. Thereby, our approach provides a foundation for an improved understanding of powerful antibiotics.
Highlights
The alarming rise of antimicrobial resistance requires antibiotics with unexploited mechanisms
The native, i.e., pharmaceutically relevant binding modes of these drugs are scarcely understood because the major technical challenges to study small drug–receptor complexes in cell membranes at the atomic level are yet to be overcome
We introduced a cutting-edge solid-state NMR (ssNMR) approach that enables comprehensive high-resolution studies of antibiotic–lipid II complexes directly in native bacterial membranes
Summary
The alarming rise of antimicrobial resistance requires antibiotics with unexploited mechanisms. Structural data on antibiotic–receptor interactions are ideally obtained under native conditions, which guarantees that the most relevant antibiotic state is studied This tenet is of special importance for antimicrobial peptides (AMPs) that target bacterial membranes, which are media of enormous complexity. We rationalize the native conformational space of lipid II-bound nisin and identify plastic domains that enable the antibiotic to adapt to the cellular environment These plastic domains correspond to pharmaceutical hotspots that allow to improve nisin’s activity, establishing a link between antimicrobial activity and cellular adaptability. These insights provide a foundation for design strategies for lipid II-targeting antibiotics and demonstrate the high potential of our native structural biology approach to obtain an improved understanding of antibiotics that target membrane constituents
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