Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins.
Mureidomycins (MRDs) A and C inhibited strongly the formation of undecaprenyl pyrophosphoryl N-acetylmuramyl-pentapeptide (lipid intermediate I), which is an intermediate in bacterial peptidoglycan synthesis (50% inhibitory concentration [IC50] of MRD A, 0.05 microgram/ml). However, they did not inhibit the formation of dolichyl pyrophosphoryl N-acetylglucosamine (Dol-p-p-GlcNAc), dolichyl phosphoryl glucose, or dolichyl phosphoryl mannose, the precursors for mammalian glycoprotein synthesis, or the formation in Bacillus subtilis of lipid-linked N-acetylglucosamine for teichoic acid synthesis (IC50s, > 100 micrograms/ml). In contrast, tunicamycin (TCM) inhibited strongly the formation of Dol-p-p-GlcNAc (IC50, 0.03 microgram/ml) but inhibited weakly the formation of bacterial lipid intermediate I (IC50, 44 micrograms/ml). When the effects of MRDs A and C and TCM on the growth of mammalian cells were compared, MRDs did not show any toxicity, even at 1,000 micrograms/ml, whereas TCM inhibited the growth of BALB/3T3 cells at 10 micrograms/ml. On the basis of these results, it was concluded that MRDs are the first specific and potent inhibitors of the translocase reaction in bacterial peptidoglycan synthesis, showing a high level of toxicity against bacteria and a low level of toxicity against mammalian cells. A specific inhibitor of translocase could be a potent antibiotic with highly selective toxicity.
Inukai
M
M
Fermentation Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Isono
F
F
Takatsuki
A
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009705:Nucleosides / Q000494:pharmacology / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology / Q000633:toxicity; D010457:Peptidoglycan / Q000096:biosynthesis* / Q000187:drug effects; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors*; D051381:Rats
D000900:Anti-Bacterial Agents; D009705:Nucleosides; D010455:Peptides; D010457:Peptidoglycan; C059803:mureidomycin A; C059805:mureidomycin C; D010458:Peptidyl Transferases