title: Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: minimal structural requirements for intermolecular complexation and fibril formation.
abstract: The peptide antibiotic ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by interrupting late-stage membrane-associated glycosyltransferase reactions catalyzed by the transglycosylase and MurG enzymes. The mechanism of ramoplanin involves sequestration of lipid-anchored PG biosynthesis intermediates, physically occluding these substrates from proper utilization by these enzymes. In this report, we describe the first molecular-level details of the interaction of ramoplanin with PG biosynthesis intermediates. NMR analysis in conjunction with chemical dissection of the PG monomer revealed that the ramoplanin octapeptide D-Hpg-D-Orn-D-alloThr-Hpg-D-Hpg-alloThr-Phe-D-Orn recognizes MurNAc-Ala-gamma-D-Glu pyrophosphate, the minimum component of PG capable of high-affinity complexation and fibril formation. Ramoplanin therefore recognizes a PG binding locus different from the N-acyl-D-Ala-D-Ala moiety targeted by vancomycin. Because ramoplanin is structurally less complex than glycopeptide antibiotics such as vancomycin, peptidomimetic chemotherapeutics derived from this recognition sequence may find future use as antibiotics against vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and related pathogens.
authors.affiliation: Johnson Research Foundation and the Department of Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA.
authors.forename: Predrag
authors.initials: P
authors.lastname: Cudic
authors.forename: James K
authors.initials: JK
authors.lastname: Kranz
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Behenna
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Kruger
authors.forename: Hellina
authors.initials: H
authors.lastname: Tadesse
authors.forename: A Joshua
authors.initials: AJ
authors.lastname: Wand
authors.forename: Yuri I
authors.initials: YI
authors.lastname: Veklich
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
authors.forename: Dewey G
authors.initials: DG
authors.lastname: McCafferty
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001412:Bacillus subtilis; D047630:Depsipeptides; D006020:Glycopeptides / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010456:Peptides, Cyclic; D010457:Peptidoglycan / Q000096:biosynthesis / Q000737:chemistry* / Q000648:ultrastructure; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D006020:Glycopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010457:Peptidoglycan; C041438:ramoplanin