Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram-negative lipid II.
Tridecaptin A1(TriA1) is a nonribosomal lipopeptide with selective antimicrobial activity against Gram-negative bacteria. Here we show that TriA1exerts 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 TriA1in 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 TriA1kills Gram-negative bacteria by a mechanism of action using a lipid-II-binding motif.
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Stephen A
SA
Cochrane
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Brandon
B
Findlay
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Alireza
A
Bakhtiary
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Jeella Z
JZ
Acedo
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Eva M
EM
Rodriguez-Lopez
National High Field NMR Centre, University of Alberta, Edmonton, AB, Canada T6G 2E1.
Pascal
P
Mercier
Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2; john.vederas@ualberta.ca.
John C
JC
Vederas
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018892:Proton-Motive Force
D000900:Anti-Bacterial Agents; D008055:Lipids; D055666:Lipopeptides; D008823:Micelles; D010455:Peptides; C017770:tridecaptins
antibiotic; lipid II; membrane pore; peptide; peptidoglycan
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