Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors.
The muraymycins, a family of nucleoside-lipopeptide antibiotics, were purified from the extract of Streptomyces sp. LL-AA896. The antibiotics were purified by chromatographic methods and characterized by NMR spectroscopy, degradation studies, and mass spectrometry. The structures of 19 compounds were established. The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety. Members of this family show broad-spectrum in vitro antimicrobial activity against a variety of clinical isolates (MIC 2 to >64 mug/mL). The muraymycins inhibited peptidoglycan biosynthesis. The fatty acid substituent and the presence or absence of the amino sugar play important roles in biological activity. One of the most active compounds, muraymycin A1, demonstrated protection in vivo against Staphylococcus aureus infection in mice (ED50 1.1 mg/kg).
McDonald
Leonard A
LA
Wyeth-Research, 401 North Middletown Road, Pearl River, New York 10965, USA. mcdonal@wyeth.com
Barbieri
Laurel R
LR
Carter
Guy T
GT
Lenoy
Eileen
E
Lotvin
Jason
J
Petersen
Peter J
PJ
Siegel
Marshall M
MM
Singh
Guy
G
Williamson
R Thomas
RT
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D010457:Peptidoglycan / Q000096:biosynthesis*; D013302:Streptomyces / Q000737:chemistry; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D014498:Uracil; D014508:Urea