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J Am Chem Soc. 2016 Jan 13;138(1):100-3. doi: 10.1021/jacs.5b11807. Epub 2015 Dec 24.

The Mechanism of Action of Lysobactin.

Author information

1
Department of Microbiology and Immunology, Harvard Medical School , Boston, Massachusetts 02115, United States.
2
Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
3
Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), and Pharmaceutical Biotechnology, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.

Abstract

Lysobactin, also known as katanosin B, is a potent antibiotic with in vivo efficacy against Staphylococcus aureus and Streptococcus pneumoniae. It was previously shown to inhibit peptidoglycan (PG) biosynthesis, but its molecular mechanism of action has not been established. Using enzyme inhibition assays, we show that lysobactin forms 1:1 complexes with Lipid I, Lipid II, and Lipid II(A)(WTA), substrates in the PG and wall teichoic acid (WTA) biosynthetic pathways. Therefore, lysobactin, like ramoplanin and teixobactin, recognizes the reducing end of lipid-linked cell wall precursors. We show that despite its ability to bind precursors from different pathways, lysobactin's cellular mechanism of killing is due exclusively to Lipid II binding, which causes septal defects and catastrophic cell envelope damage.

PMID:
26683668
PMCID:
PMC4817722
DOI:
10.1021/jacs.5b11807
[Indexed for MEDLINE]
Free PMC Article

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