A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface.
The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Gram-positive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimetics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 A. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.
Hamburger
James B
JB
Department of Chemistry, Duke University, Durham, NC 27708, USA.
Hoertz
Amanda J
AJ
Lee
Amy
A
Senturia
Rachel J
RJ
McCafferty
Dewey G
DG
Loll
Patrick J
PJ
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D018360:Crystallography, X-Ray / Q000379:methods; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology; D019281:Dimerization; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000378:metabolism; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D008024:Ligands; D008055:Lipids; D010455:Peptides; C041438:ramoplanin