Mode of action of teixobactins in cellular membranes



Shukla, Rhythm, Medeiros-Silva, Joao, Parmar, Anish, Vermeulen, Bram JA, Das, Sanjit, Paioni, Alessandra Lucini, Jekhmane, Shehrazade, Lorent, Joseph, Bonvin, Alexandre MJJ, Baldus, Marc
et al (show 5 more authors) (2020) Mode of action of teixobactins in cellular membranes. Nature Communications, 11 (1).

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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.

Item Type: Article
Uncontrolled Keywords: antibiotics, bacterial infection, drug discovery and development, solid-state NMR
Depositing User: Symplectic Admin
Date Deposited: 08 Jun 2020 09:15
Last Modified: 05 Oct 2022 22:06
DOI: 10.1038/s41467-020-16600-2
Open Access URL: https://www.nature.com/articles/s41467-020-16600-2
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3089756