As reported previously,1,2) globomycin, a new cyclic peptide antibiotic, is active against certain Gram-negative bacteria (e.g. Escherichia coli, Klebsiella pneumoniae and Shigella), but inactive against Pseudomonas, Proteus, and Gram-positive bacteria. Formation of spheroplasts was observed when E. coli was grown in the presence of globomycin, indicating that it inhibits bacterial cell wall synthesis.
Using a continuous fluorescence-based enzyme assay, we have characterized the antibacterial agents tumicamycin and liposidomycin B as inhibitors of solubilized Escherichia coli phospho-N-acetylmuramyl-pentapeptide translocase. Tunicamycin exhibited reversible inhibition (Ki = 0.55 +/- 0.1 microM) which was noncompetitive with respect to the lipid acceptor substrate and competitive with respect to the fluorescent substrate analog, dansyl-UDPMurNAc-pentapeptide. Liposidomycin B exhibited slow-binding inhibition (Ki = 80 +/- 15 nM) which was competitive with respect to the lipid acceptor substrate and noncompetitive with respect to dansyl-UDPMurNAc-pentapeptide. These results provide insight into the molecular mechanisms of action of these two classes of nucleoside antibiotics.
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.
Mureidomycins (MRD's) A~D were specifically active against Pseudomonas aeruginosa. Amongthem, MRDC was most active, with MICs of 0.1 to 3.13 /^g/ml against many strains of the target organism. Its activity was comparable to that of cefoperazone, ceftazidime and cefsulodin. MRD C-resistant mutants of P. aeruginosa appeared spontaneously at a high frequency whencultured in the presence of the antibiotic. Nocross-resistance was observed with /3-lactam antibiotics. A rapid decrease of turbidity along with spheroplast formation and cell lysis was observed whencells of P. aeruginosa were grownin the presence of MRD C. The compoundsexhibited low toxicity and protected mice from experimental infection with P. aeruginosa. The urinary and fecal recoveries of MRDC given subcutaneously were 5 and 18%, respectively. Although many new /3-lactam antibiotics with activity against Pseudomonas aeruginosa have been synthesized, the infectious diseases caused by this species of bacteria still pose serious problems throughout the world.
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