Abstract
Lipid II is an essential precursor for bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Several lanthionine-containing peptide antibiotics target lipid II with lanthionine-stabilized lipid II binding motifs. Here, we used the biosynthesis system of the lantibiotic nisin to synthesize a two-lipid II binding motifs-containing lantibiotic, termed TL19, which contains the N-terminal lipid II binding motif of nisin and the distinct C-terminal lipid II binding motif of one peptide of the two-component haloduracin (i.e., HalA1). Further characterization demonstrated that (i) TL19 exerts 64-fold stronger antimicrobial activity against Enterococcus faecium than nisin(1-22), which has only one lipid II binding site, and (ii) both the N- and C-terminal domains are essential for the potent antimicrobial activity of TL19, as evidenced by mutagenesis of each single and the double domains. These results show the feasibility of a new approach to synthesize potent lantibiotics with two different lipid II binding motifs to treat specific antibiotic-resistant pathogens.
Highlights
Lipid II is an essential precursor for bacterial cell wall biosynthesis and thereby an important target for various antibiotics
No adducts were observed for the TL19 main product, indicating that all cysteines had reacted with dehydroamino acids to formlanthionines (Fig. 2b)
The lipid II binding motif of this class of antibiotics is essential for their potent antimicrobial activity (13, 15)
Summary
Lipid II is an essential precursor for bacterial cell wall biosynthesis and thereby an important target for various antibiotics. Two of the modified candidates (TL17 and TL19) showed potent antimicrobial activity against Micrococcus flavus (see Fig. S1 in the supplemental material), and both of these peptides were correctly dehydrated as predicted (Table 1). In the MIC assays, nisin was used as a well-known antibiotic control, and nisin(1-22) was used as a one-lipid II binding motif-containing lantibiotic control with relatively low aac.asm.org 3
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