Year: 2018
Type: article
Abstract: Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal "cage" and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a β conformation that is highly prone to aggregation, which likely contributes to the antibiotic's high bactericidal efficiency. Overall, our study provides several new clues to teixobactin's modes of action.
Source: Chemical Science
DOI: 10.1039/c8sc03655a
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
Funders: Bill and Melinda Gates Foundation, European Commission, University of California, San Francisco, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, National Institute of General Medical Sciences, H2020 European Research Council, FP7 People: Marie-Curie Actions
Awards: G1011362930, NovoBiotic Pharmaceuticals, LLC - to identify new compounds with specific activity against M. tuberculosis, which increases the likelihood of treating the disease while leaving the ..., Elucidating and exploiting docking domain-mediated carrier protein recognition in natural product megasynthetases, G1907146399, G2328413355, G3077243175, G3207356259, Resource for Biocomputing Visualization and Informatics, G3928546238, NovoBiotic Pharmaceuticals, LLC - to develop a drug candidate for oral treatment of tuberculosis, G4053127980, G442989154, G4626508987, G4815039349, Biophysical basis for the chain termination in the enacyloxin polyketide synthase, Cross-scale prediction of Antimicrobial Resistance: from molecules to populations., G5294354809, G5602792140, Structural Dynamics of Protein Complexes by Solid-State NMR, Centre for Integrative Theoretical and Experimental Analytical Science for Application to Bacterial Cell Division and Quality by Design, G6285642246, 100 kHz magic angle spinning for development of solid-state NMR methodology for probing protein dynamics, G7401113806, G7546946110, G7598153673, G7978619729, G8761489887, G896728979
OpenAlex ID: W2892266268