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.
Pharmaceutical Microbiology Section, Institute for Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53115 Bonn, Germany.
Tanja
T
Schneider
Thomas
T
Kruse
Reinhard
R
Wimmer
Imke
I
Wiedemann
Vera
V
Sass
Ulrike
U
Pag
Andrea
A
Jansen
Allan K
AK
Nielsen
Per H
PH
Mygind
Dorotea S
DS
Raventós
Søren
S
Neve
Birthe
B
Ravn
Alexandre M J J
AM
Bonvin
Leonardo
L
De Maria
Anders S
AS
Andersen
Lora K
LK
Gammelgaard
Hans-Georg
HG
Sahl
Hans-Henrik
HH
Kristensen
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