Antibacterial activity of synthetic analogues based on the disaccharide structure of moenomycin, an inhibitor of bacterial transglycosylase

Moenomycin is a natural product glycolipid that inhibits the growth of a br oad spectrum of Gram-positive bacteria. In Escherichia coli, moenomycin inh ibits peptidoglycan synthesis at the transglycosylation stage, causes accum ulation of cell-wall intermediates, and leads to lysis and cell death. Howe ver, unlike Esc. coli, where 5-6 log units of killing are observed, 0-2 log units of killing occurred when Gram-positive bacteria were treated with si milar multiples of the MIC. In addition, bulk peptidoglycan synthesis in in tact Cram-positive cells was resistant to the effects of moenomycin. In con trast, synthetic disaccharides based on the moenomycin disaccharide core st ructure were identified that were bactericidal to Gram-positive bacteria, i nhibited cell-wall synthesis in intact cells, and were active on both sensi tive and vancomycin-resistant enterococci. These disaccharide analogues do not inhibit the formation of N-acetylglucosamine-beta -1,4-MurNAc-pentape u ndecaprenol (lipid II), but do inhibit the polymerization of lipid II into peptidoglycan in Esc. coli. In addition, cell growth was required for bacte ricidal activity. The data indicate that synthetic disaccharide analogues o f moenomycin inhibit cell-wall synthesis at the transglycosylation stage, a nd that their activity on Gram-positive bacteria differs from moenomycin du e to differential targeting of the transglycosylation process. Inhibition o f the transglycosylation process represents a promising approach to the des ign of new antibacterial agents active on drug-resistant bacteria.