Visualizing the mode of action and supramolecular assembly of teixobactin analogues in Bacillus subtilis

Abstract

Teixobactin has been the source of intensive study and interest as a promising antibiotic, because of its excellent activity against drug-resistant Gram-positive pathogens and its novel but not yet fully understood mechanism of action that precludes drug resistance. Recent studies have demonstrated that the mode of action of teixobactin is more complicated than initially thought, with supramolecular assembly of the antibiotic appearing to play a critical role in the binding process. Further studies of the interactions of teixobactin with bacteria and its molecular targets offer the promise of providing deeper insights into its novel mechanism of action and guiding the design of additional drug candidates and analogues. The current study reports the preparation and study of teixobactin analogues bearing a variety of fluorophores. Structured illumination microscopy of the fluorescent teixobactin analogues with B. subtilis enables super-resolution visualization of the interaction of teixobactin with bacterial cell walls and permits the observation of aggregated clusters of the antibiotic on the bacteria. Förster resonance energy transfer (FRET) microscopy further elucidates the supramolecular assembly by showing that fluorescent teixobactin molecules co-localize within a few nanometers on B. subtilis. Fluorescence microscopy over time with a fluorescent teixobactin analogue and propidium iodide in B. subtilis reveals a correlation between cell death and binding of the antibiotic to cellular targets, followed by lysis of cells. Collectively, these studies provide new insights into the binding of teixobactin to Gram-positive bacteria, its supramolecular mechanism of action, and the lysis of bacteria that follows.

Graphical abstract: Visualizing the mode of action and supramolecular assembly of teixobactin analogues in Bacillus subtilis

Supplementary files

Article information

Article type
Edge Article
Submitted
08 Mar 2022
Accepted
11 May 2022
First published
13 May 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2022, Advance Article

Visualizing the mode of action and supramolecular assembly of teixobactin analogues in Bacillus subtilis

M. A. Morris, A. Vallmitjana, F. Grein, T. Schneider, M. Arts, C. R. Jones, B. T. Nguyen, M. H. Hashemian, M. Malek, E. Gratton and J. S. Nowick, Chem. Sci., 2022, Advance Article , DOI: 10.1039/D2SC01388F

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