Plectasin, a fungal defensin, targets the bacterial cell wall precursor Lipid II.
Host defense peptides such as defensins are components of innate immunity and have retained antibiotic activity throughout evolution. Their activity is thought to be due to amphipathic structures, which enable binding and disruption of microbial cytoplasmic membranes. Contrary to this, we show that plectasin, a fungal defensin, acts by directly binding the bacterial cell-wall precursor Lipid II. A wide range of genetic and biochemical approaches identify cell-wall biosynthesis as the pathway targeted by plectasin. In vitro assays for cell-wall synthesis identified Lipid II as the specific cellular target. Consistently, binding studies confirmed the formation of an equimolar stoichiometric complex between Lipid II and plectasin. Furthermore, key residues in plectasin involved in complex formation were identified using nuclear magnetic resonance spectroscopy and computational modeling.
Schneider
Tanja
T
Pharmaceutical Microbiology Section, Institute for Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53115 Bonn, Germany.
Kruse
Thomas
T
Wimmer
Reinhard
R
Wiedemann
Imke
I
Sass
Vera
V
Pag
Ulrike
U
Jansen
Andrea
A
Nielsen
Allan K
AK
Mygind
Per H
PH
Raventós
Dorotea S
DS
Neve
Søren
S
Ravn
Birthe
B
Bonvin
Alexandre M J J
AM
De Maria
Leonardo
L
Andersen
Anders S
AS
Gammelgaard
Lora K
LK
Sahl
Hans-Georg
HG
Kristensen
Hans-Henrik
HH
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001203:Ascomycota / Q000737:chemistry; D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism*; D003198:Computer Simulation; D023082:Defensins / Q000378:metabolism* / Q000494:pharmacology; D005656:Fungal Proteins / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D013210:Staphylococcus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D023082:Defensins; D005656:Fungal Proteins; D010455:Peptides; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C504857:plectasin; D014640:Vancomycin