Functional analysis of the lipoglycodepsipeptide antibiotic ramoplanin.
The peptide antibiotic ramoplanin is highly effective against several drug-resistant gram-positive bacteria, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by binding to Lipid intermediates I and II at a location different than the N-acyl-D-Ala-D-Ala dipeptide site targeted by vancomycin. Lipid I/II capture physically occludes these substrates from proper utilization by the late-stage PG biosynthesis enzymes MurG and the transglycosylases. Key structural features of ramoplanin responsible for antibiotic activity and PG molecular recognition have been discovered by antibiotic semisynthetic modification in conjunction with NMR analyses. These results help define a minimalist ramoplanin pharmacophore and introduce the possibility of generating ramoplanin-derived peptide or peptidomimetic antibiotics for use against VRE, MRSA, and related pathogens.
Cudic
Predrag
P
Johnson Research Foundation, Department of Biochemistry and Biophysics, Philadelphia, PA 19104, USA.
Behenna
Douglas C
DC
Kranz
James K
JK
Kruger
Ryan G
RG
Wand
A Joshua
AJ
Veklich
Yuri I
YI
Weisel
John W
JW
McCafferty
Dewey G
DG
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D047630:Depsipeptides; D019281:Dimerization; D015195:Drug Design; D004355:Drug Stability; D006031:Glycosylation; D008968:Molecular Conformation; D009952:Ornithine; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D010457:Peptidoglycan / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D010457:Peptidoglycan; C041438:ramoplanin; D009952:Ornithine