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High-resolution NMR studies of antibiotics in cellular membranes

Medeiros-Silva, João and Jekhmane, Shehrazade and Paioni, Alessandra Lucini and Gawarecka, Katarzyna and Marc Baldus, Marc and Swiezewska, Ewa and Breukink, Eefjan and Weingarth, Markus (2018) High-resolution NMR studies of antibiotics in cellular membranes. Nature Communications, 9 (1). p. 3963. ISSN 2041-1723



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 rembraneembedded 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.

Item Type:Article
Subjects:Q Science > QH Natural history > QH301 Biology
Divisions:Department of Lipid Biochemistry
ID Code:1598
Deposited By: Ewa Swiezewska
Deposited On:19 Oct 2018 13:22
Last Modified:19 Oct 2018 13:22

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