Complexation of Peptidoglycan Intermediates by the Lipoglycodepsipeptide Antibiotic Ramoplanin: Minimal Structural Requirements for Intermolecular Complexation and Fibril Formation

Complexation of Peptidoglycan Intermediates by the Lipoglycodepsipeptide Antibiotic Ramoplanin: Minimal Structural Requirements for Intermolecular Complexation and Fibril Formation

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 i...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 11; pp. 7384 - 7389
Main Authors: Cudic, Predrag, Kranz, James K., Behenna, Douglas C., Kruger, Ryan G., Tadesse, Hellina, Wand, A. Joshua, Veklich, Yuri I., Weisel, John W., McCafferty, Dewey G.
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 28-05-2002
National Acad Sciences
The National Academy of Sciences
Subjects:
Amino Acid Sequence
Anti-Bacterial Agents - chemistry
Antibiotics
Bacillus subtilis
Biological Sciences
Biosynthesis
Chemical equilibrium
Depsipeptides
Diphosphates
Glycopeptides
Glycopeptides - chemistry
Lipids
Magnetic Resonance Spectroscopy
Microscopy, Electron
Models, Molecular
Molecular Sequence Data
Nucleotides
Peptide Fragments - chemistry
Peptides, Cyclic
Peptidoglycan - biosynthesis
Peptidoglycan - chemistry
Peptidoglycan - ultrastructure
Protein Conformation
Protons
Solar fibrils
Titration
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Summary: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-γ-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.
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To whom reprint requests should be addressed at: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 905A Stellar-Chance Building, 422 Curie Boulevard, Philadelphia, PA 19104-6059. E-mail: deweym@mail.med.upenn.edu.
Communicated by William F. DeGrado, University of Pennsylvania School of Medicine, Philadelphia, PA
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.102192099