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Peer-reviewedCC BY-NCChemical science

A siderophore-independent lanthipeptide carrier enables Trojan-horse delivery of antibacterial cargoes into Gram-negative bacteria.

  • Boning Wang1
  • Yundan Zheng1
  • Erpeng Guo2
  • Yewen Juan1
  • Yida Han1
  • Yuqing Li1
  • Yeying Ma1
  • Wenya Zhou1
  • Xu Zhen1
  • Ran Xie1
  • Tong Si2
  • Huan Wang1,3
  1. 1School of Chemistry, Nanjing Drum Tower Hospital, State Key Laboratory of Coordination Chemistry, Nanjing University Nanjing 210023 China [email protected].
  2. 2State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences Shenzhen 518055 China [email protected].
  3. 3Chemistry and Biomedicine Innovation Center of Nanjing University Nanjing 210023 China.
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Abstract

The Gram-negative outer membrane restricts the accumulation of many antibacterial agents. Expanding the repertoire of Trojan horse carriers could provide delivery strategies that complement established siderophore-based systems. Here, we report that noursin, a tricyclic lanthipeptide containing labionin and histidinobutyrine crosslinks, functions as a carrier for Gram-negative bacterial delivery. Noursin showed cell-associated accumulation in diverse Gram-negative bacteria. Accumulation was retained in mutants lacking TonB or selected siderophore receptors, while deletion and complementation experiments identified SbmA and YbgH as positive contributors to NBD-noursin accumulation. Conjugation to noursin promoted bacterial accumulation of two chemically distinct photosensitizers and enabled light-dependent killing. Photosensitizer-noursin retained accumulation and photodynamic activity in TonB-deficient Escherichia coli and enhanced cefiderocol activity under co-treatment conditions. These results establish noursin as a functional lanthipeptide-derived Trojan horse carrier and highlight structurally complex RiPPs as underexplored delivery scaffolds for combating Gram-negative bacterial pathogens.

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Cite

BibTeXRIS
BibTeX
@article{wang2026siderophoreindependent,
  title = {{A siderophore-independent lanthipeptide carrier enables Trojan-horse delivery of antibacterial cargoes into Gram-negative bacteria.}},
  author = {Boning Wang and Yundan Zheng and Erpeng Guo and Yewen Juan and Yida Han and Yuqing Li and Yeying Ma and Wenya Zhou and Xu Zhen and Ran Xie and Tong Si and Huan Wang},
  journal = {Chemical science},
  year = {2026},
  month = oct,
  doi = {10.1039/d6sc05931g},
  url = {https://europepmc.org/article/MED/42924109},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - A siderophore-independent lanthipeptide carrier enables Trojan-horse delivery of antibacterial cargoes into Gram-negative bacteria.
AU  - Boning Wang
AU  - Yundan Zheng
AU  - Erpeng Guo
AU  - Yewen Juan
AU  - Yida Han
AU  - Yuqing Li
AU  - Yeying Ma
AU  - Wenya Zhou
AU  - Xu Zhen
AU  - Ran Xie
AU  - Tong Si
AU  - Huan Wang
PY  - 2026
DA  - 2026/10/20
JO  - Chemical science
DO  - 10.1039/d6sc05931g
UR  - https://europepmc.org/article/MED/42924109
AB  - The Gram-negative outer membrane restricts the accumulation of many antibacterial agents. Expanding the repertoire of Trojan horse carriers could provide delivery strategies that complement established siderophore-based systems. Here, we report that noursin, a tricyclic lanthipeptide containing labionin and histidinobutyrine crosslinks, functions as a carrier for Gram-negative bacterial delivery. Noursin showed cell-associated accumulation in diverse Gram-negative bacteria. Accumulation was retained in mutants lacking TonB or selected siderophore receptors, while deletion and complementation experiments identified SbmA and YbgH as positive contributors to NBD-noursin accumulation. Conjugation to noursin promoted bacterial accumulation of two chemically distinct photosensitizers and enabled light-dependent killing. Photosensitizer-noursin retained accumulation and photodynamic activity in TonB-deficient Escherichia coli and enhanced cefiderocol activity under co-treatment conditions. These results establish noursin as a functional lanthipeptide-derived Trojan horse carrier and highlight structurally complex RiPPs as underexplored delivery scaffolds for combating Gram-negative bacterial pathogens.
SN  - 2041-6520
SN  - 2041-6539
ER  -