Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. Antimicrob. Agents Chemother

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%o inhibitory concentration [IC50] of MRD A, 0.05,ug/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 BaciUlus subtilis of lipid-linked N-acetylglucosamine for teichoic acid synthesis (IC50s,> 100 p,g/ml). In contrast, tunicamycin (TCM) inhibited strongly the formation of Dol-p-p-GlcNAc (IC50, 0.03,ugIml) but inhibited weakly the formation of bacterial lipid intermediate I (IC50, 44,ug/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,ug/ml, whereas TCM inhibited the growth of BALB/3T3 cells at 10,ug/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. The novel peptidylnucleoside antibiotics mureidomycins (MRDs) A and C (Fig. 1), are structurally new types o