Mureidomycins A-D, novel peptidylnucleoside antibiotics with spheroplast forming activity. III. Biological properties.

Abstract

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.

Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis

“…As it was supposed that MRD would inhibit peptidoglycan synthesis of P. aeruginosa from the results reported in a previous study (5), an in vitro peptidoglycansynthesizing system was constructed, using ether-treated P. aeruginosa cells as an enzyme source. It is well-known that precursors of peptidoglycan synthesis, such as UDPMurNAc-pentapeptide and UDP-GlcNAc, are permeable in ether-treated cells (9,10).…”

“…They are composed of four structurally related components, designated A, B, C, and D (4), that have low toxicity and are effective against P. aeruginosa infections in mice (5). In a previous paper, we reported that mureidomycin A (MRD) induced spheroplast formation followed by cell lysis of P. aeruginosa at the MIC.…”

Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action

“…Examples of spheroplast-inducing disruptors of peptidoglycan synthesis outside the β-lactam class include the MurA inhibitor fosfomycin [73], the MurC inhibitor glycine [74,87], the Alr and Ddl inhibitor cycloserine [73], the MraY inhibitor mureidomycin [73,88], the D-alanyl-D-alanine binding antibiotic vancomycin [89], the transglycosylase inhibitors ensanchomycin, prenomycin [73], and moenomycin [90], and the transpeptidase inhibitor lactivicin [91]. Depriving cells of diaminopimelic acid [57] or inhibiting its incorporation into the cell wall using malioxamycin [73] also triggers spheroplast formation.…”

Phospho- N -Acetyl-Muramyl-Pentapeptide Translocase from Escherichia coli : Catalytic Role of Conserved Aspartic Acid Residues

“…Several nucleoside natural product antibiotics that contain the uridine moiety of the natural substrate of translocase 1 have been shown to be potent inhibitors of this enzyme, namely, the mureidomycins, the liposidomycins, tunicamycin, and, most recently, the muramycins (12,13,28,29,32,37). The latter class of compounds are growth inhibitory towards both gram-positive and gram-negative pathogens (37), whereas the mureidomycins show selective activity against Pseudomonas species (30).…”