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Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11561-11566. Epub 2016 Sep 29.

Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram-negative lipid II.

Author information

1
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
2
National High Field NMR Centre, University of Alberta, Edmonton, AB, Canada T6G 2E1.
3
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2; john.vederas@ualberta.ca.

Abstract

Tridecaptin A1 (TriA1) is a nonribosomal lipopeptide with selective antimicrobial activity against Gram-negative bacteria. Here we show that TriA1 exerts its bactericidal effect by binding to the bacterial cell-wall precursor lipid II on the inner membrane, disrupting the proton motive force. Biochemical and biophysical assays show that binding to the Gram-negative variant of lipid II is required for membrane disruption and that only the proton gradient is dispersed. The NMR solution structure of TriA1 in dodecylphosphocholine micelles with lipid II has been determined, and molecular modeling was used to provide a structural model of the TriA1-lipid II complex. These results suggest that TriA1 kills Gram-negative bacteria by a mechanism of action using a lipid-II-binding motif.

KEYWORDS:

antibiotic; lipid II; membrane pore; peptide; peptidoglycan

PMID:
27688760
PMCID:
PMC5068289
DOI:
10.1073/pnas.1608623113
[Indexed for MEDLINE]
Free PMC Article

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