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Structural studies suggest aggregation as one of the modes of action for teixobactin

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Öster, Carl, Walkowiak, Grzegorz P., Hughes, Dallas E., Spoering, Amy L., Peoples, Aaron J., Catherwood, Anita C., Tod, Julie A., Lloyd, Adrian J., Herrmann, Torsten, Lewis, Kim, Dowson, Christopher G. and Lewandowski, Józef R. (2018) Structural studies suggest aggregation as one of the modes of action for teixobactin. Chemical Science, 9 (47). pp. 8850-8859. doi:10.1039/c8sc03655a ISSN 2041-6520.

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Official URL: https://doi.org/10.1039/c8sc03655a

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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 b 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.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH): Antibiotics, Biosynthesis, Lipids, Nuclear magnetic resonance, Drug resistance in microorganisms
Journal or Publication Title: Chemical Science
Publisher: Royal Society of Chemistry
ISSN: 2041-6520
Official Date: 21 December 2018
Dates:
DateEvent
21 December 2018Published
28 September 2018Available
19 September 2018Accepted
16 August 2018Modified
15 June 2018Submitted
Volume: 9
Number: 47
Page Range: pp. 8850-8859
DOI: 10.1039/c8sc03655a
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 1 October 2018
Date of first compliant Open Access: 1 October 2018
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
OPP1160394Bill and Melinda Gates Foundationhttp://dx.doi.org/10.13039/100000865
OPP1132809Bill and Melinda Gates Foundationhttp://dx.doi.org/10.13039/100000865
639907 Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
EP/L025906/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/L022761/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R010218/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
MR/N002679/1Antimicrobial Resistance CentreUNSPECIFIED
316630 CAS-IDPFP7 People: Marie-Curie Actionshttp://dx.doi.org/10.13039/100011264
IGMS P41-GM103311University of California, Los Angeleshttp://dx.doi.org/10.13039/100007185
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