Mode of action of teixobactins in cellular membranes

Rhythm Shukla, João Medeiros-Silva, Anish Parmar, Bram J. A. Vermeulen, Sanjit Das, Alessandra Lucini Paioni, Shehrazade Jekhmane, Joseph Lorent, Alexandre M. J. J. Bonvin, Marc Baldus, Moreno Lelli, Edwin J. A. Veldhuizen, Eefjan Breukink, Ishwar Singh and Markus Weingarth ()
Additional contact information
Rhythm Shukla: Utrecht University
João Medeiros-Silva: Utrecht University
Anish Parmar: University of Lincoln
Bram J. A. Vermeulen: Utrecht University
Sanjit Das: University of Lincoln
Alessandra Lucini Paioni: Utrecht University
Shehrazade Jekhmane: Utrecht University
Joseph Lorent: Utrecht University
Alexandre M. J. J. Bonvin: Utrecht University
Marc Baldus: Utrecht University
Moreno Lelli: University of Florence
Edwin J. A. Veldhuizen: Utrecht University
Eefjan Breukink: Utrecht University
Ishwar Singh: University of Lincoln
Markus Weingarth: Utrecht University

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.

Date: 2020
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DOI: 10.1038/s41467-020-16600-2

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