SELECTIVE-INHIBITION OF THE BACTERIAL TRANSLOCASE REACTION IN PEPTIDOGLYCAN SYNTHESIS BY MUREIDOMYCINS

Mureidomycins (MRDs) A and C inhibited strongly the formation of undec aprenyl pyrophosphoryl N-acetylmuramyl-pentapeptide (lipid intermediat e 1), which is an intermediate in bacterial peptidoglycan synthesis (5 0% inhibitory concentration [IC50] of MRD A, 0.05 mug/ml). However, th ey did not inhibit the formation of dolichyl pyrophosphoryl N-acetylgl ucosamine (Dol-p-p-GlcNAc), dolichyl phosphoryl glucose, or dolichyl p hosphoryl mannose, the precursors for mammalian glycoprotein synthesis , or the formation in Bacillus subtilis of lipid-linked N-acetylglucos amine for teichoic acid synthesis (IC50s, > 100 mug/ml). In contrast, tunicamycin (TCM) inhibited strongly the formation of Dol-p-p-GlcNAc ( IC50, 0.03 mug/ml) but inhibited weakly the formation of bacterial lip id intermediate I (IC50, 44 mug/ml). When the effects of MRDs A and C and TCM on the growth of mammalian cells were compared, MRDs did not s how any toxicity, even at 1,000 mug/ml, whereas TCM inhibited the grow th of BALB/3T3 cells at 10 mug/ml. On the basis of these results, it w as concluded that MRDs are the first specific and potent inhibitors of the translocase reaction in bacterial peptidoglycan synthesis, showin g a high level of toxicity against bacteria and a low level of toxicit y against mammalian cells. A specific inhibitor of translocase could b e a potent antibiotic with highly selective toxicity.