Inhibition of peptidoglycan biosynthesis in gram-positive bacteria by LY146032.
LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megaterium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.
Allen
N E
NE
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Hobbs
J N
JN
Alborn
W E
WE
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D017576:Daptomycin; D010455:Peptides / Q000494:pharmacology; D010457:Peptidoglycan / Q000096:biosynthesis*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives / Q000378:metabolism
D000900:Anti-Bacterial Agents; D010455:Peptides; D010457:Peptidoglycan; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C002225:UDP-N-acetylmuramic acid pentapeptide; D017576:Daptomycin