The lipopeptide antibiotic Friulimicin B inhibits cell wall biosynthesis through complex formation with bactoprenol phosphate.
Friulimicin B is a naturally occurring cyclic lipopeptide, produced by the actinomycete Actinoplanes friuliensis, with excellent activity against gram-positive pathogens, including multidrug-resistant strains. It consists of a macrocyclic decapeptide core and a lipid tail, interlinked by an exocyclic amino acid. Friulimicin is water soluble and amphiphilic, with an overall negative charge. Amphiphilicity is enhanced in the presence of Ca(2+), which is also indispensable for antimicrobial activity. Friulimicin shares these physicochemical properties with daptomycin, which is suggested to kill gram-positive bacteria through the formation of pores in the cytoplasmic membrane. In spite of the fact that friulimicin shares features of structure and potency with daptomycin, we found that friulimicin has a unique mode of action and severely affects the cell envelope of gram-positive bacteria, acting via a defined target. We found friulimicin to interrupt the cell wall precursor cycle through the formation of a Ca(2+)-dependent complex with the bactoprenol phosphate carrier C(55)-P, which is not targeted by any other antibiotic in use. Since C(55)-P also serves as a carrier in teichoic acid biosynthesis and capsule formation, it is likely that friulimicin blocks multiple pathways that are essential for a functional gram-positive cell envelope.
Schneider
T
T
Institute of Pharmaceutical Microbiology, Pharmaceutical Microbiology Section, University of Bonn, Bonn, Germany. tanja@mibi03.meb.uni-bonn.de
Gries
K
K
Josten
M
M
Wiedemann
I
I
Pelzer
S
S
Labischinski
H
H
Sahl
H-G
HG
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D013210:Staphylococcus / Q000187:drug effects; D013729:Terpenes / Q000378:metabolism*; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives / Q000378:metabolism
D000900:Anti-Bacterial Agents; D010455:Peptides; D013729:Terpenes; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C000146:bactoprenol; C002225:UDP-N-acetylmuramic acid pentapeptide; C416818:friulimicin B