Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: minimal structural requirements for intermolecular complexation and fibril formation.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Cudic, P; Kranz, JK; Behenna, DC; Kruger, RG; Tadesse, H; Wand, AJ; Veklich, YI; Weisel, JW; McCafferty, DG
Published Date
- May 2002
Published In
Volume / Issue
- 99 / 11
Start / End Page
- 7384 - 7389
PubMed ID
- 12032292
Pubmed Central ID
- PMC124240
Electronic International Standard Serial Number (EISSN)
- 1091-6490
International Standard Serial Number (ISSN)
- 0027-8424
Digital Object Identifier (DOI)
- 10.1073/pnas.102192099
Language
- eng