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

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.