Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation

Patrick J. Knerr, Trent J. Oman, Chantal V. Garcia De Gonzalo, Tania Lupoli, Suzanne Walker, Wilfred A. Van Der Donk

Research output: Contribution to journalArticle

Abstract

Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products that contain the thioether structures lanthionine and methyllanthionine and exert potent antimicrobial activity against Gram-positive bacteria. At present, detailed modes-of-action are only known for a small subset of family members. Lacticin 481, a tricyclic lantibiotic, contains a lipid II binding motif present in related compounds such as mersacidin and nukacin ISK-1. Here, we show that lacticin 481 inhibits PBP1b-catalyzed peptidoglycan formation. Furthermore, we show that changes in potency of analogues of lacticin 481 containing non-proteinogenic amino acids correlate positively with the potency of inhibition of the transglycosylase activity of PBP1b. Thus, lipid II is the likely target of lacticin 481, and use of non-proteinogenic amino acids resulted in stronger inhibition of the target. Additionally, we demonstrate that lacticin 481 does not form pores in the membranes of susceptible bacteria, a common mode-of-action of other lantibiotics.

Original languageEnglish (US)
Pages (from-to)1791-1795
Number of pages5
JournalACS Chemical Biology
Volume7
Issue number11
DOIs
StatePublished - Nov 16 2012

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Peptidoglycan
Bacteriocins
Amino Acids
Bacteria
Gram-Positive Bacteria
Sulfides
Biological Products
lacticin 481
Inhibition (Psychology)
Membranes
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation. / Knerr, Patrick J.; Oman, Trent J.; Garcia De Gonzalo, Chantal V.; Lupoli, Tania; Walker, Suzanne; Van Der Donk, Wilfred A.

In: ACS Chemical Biology, Vol. 7, No. 11, 16.11.2012, p. 1791-1795.

Research output: Contribution to journalArticle

Knerr, Patrick J. ; Oman, Trent J. ; Garcia De Gonzalo, Chantal V. ; Lupoli, Tania ; Walker, Suzanne ; Van Der Donk, Wilfred A. / Non-proteinogenic amino acids in lacticin 481 analogues result in more potent inhibition of peptidoglycan transglycosylation. In: ACS Chemical Biology. 2012 ; Vol. 7, No. 11. pp. 1791-1795.
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