An Engineered Double Lipid II Binding Motifs-Containing Lantibiotic Displays Potent and Selective Antimicrobial Activity against Enterococcus faecium

Xinghong Zhao, Zhongqiong Yin, Eefjan Breukink, Gert N. Moll, Oscar P. Kuipers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)
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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.

Original languageEnglish
Article number e02050-19
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number6
Early online date2020
DOIs
Publication statusPublished - Jun-2020

Keywords

  • Enterococcus
  • Lactococcus
  • haloduracin
  • lantibiotic
  • lipid II
  • nisin
  • LACTOCOCCUS-LACTIS
  • NISIN
  • BIOSYNTHESIS
  • PRECURSOR
  • MECHANISM
  • PEPTIDES
  • LACTICIN-3147
  • BACTERIOCINS
  • DISCOVERY
  • BLUEPRINT

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