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

Abstract

Moenomycin is a natural product glycolipid that inhibits the growth of a broad spectrum of Gram-positive bacteria. In Escherichia coli, moenomycin inhibits peptidoglycan synthesis at the transglycosylation stage, causes accumulation of cell-wall intermediates, and leads to lysis and cell death. However, 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 similar multiples of the MIC. In addition, bulk peptidoglycan synthesis in intact Gram-positive cells was resistant to the effects of moenomycin. In contrast, synthetic disaccharides based on the moenomycin disaccharide core structure were identified that were bactericidal to Gram-positive bacteria, inhibited cell-wall synthesis in intact cells, and were active on both sensitive and vancomycinresistant enterococci. These disaccharide analogues do not inhibit the formation of N-acetylglucosamine-β-1,4-MurNAc-pentapeptide-pyrophosphorylundecaprenol (lipid II), but do inhibit the polymerization of lipid II into peptidoglycan in Esc. coli. In addition, cell growth was required for bactericidal activity. The data indicate that synthetic disaccharide analogues of moenomycin inhibit cell-wall synthesis at the transglycosylation stage, and that their activity on Gram-positive bacteria differs from moenomycin due to differential targeting of the transglycosylation process. Inhibition of the transglycosylation process represents a promising approach to the design of new antibacterial agents active on drug-resistant bacteria.

ZipA Is Required for FtsZ-Dependent Preseptal Peptidoglycan Synthesis prior to Invagination during Cell Division

“…It was possible, as was suggested by Nanninga (48), that preseptal peptidoglycan synthesis might require one or more penicillin-insensitive peptidoglycan synthases instead of PBP1a and -1b. The known candidates for such an activity in E. coli are PBP1c (56,69) and MtgA (4,24,25). Because these enzymes exhibit only glycosyltransferase activity, they can polymerize but not cross-link glycan strands.…”

Biocidal Properties of a Glycosylated Surface: Sophorolipids on Au(111)

“…48 Similar arguments are also used to explain the mechanism of action of the moenomycin antibiotic, a well-known glycolipid, and its derivatives. They inhibit the in vitro transglycosylation reaction in E. coli, thus blocking the synthesis of the cell wall and its eventual death, with or without lysis [49][50][51] . In addition, a potential role as signaling molecules that regulate gene expression has been discussed to explain the antiadhesive properties of some bacterial exopolysaccharides 16 .…”

Characterization of moenomycin antibiotic complex by multistage MALDI-IT/RTOF-MS and ESI-IT-MS

“…Although several antibiotics interfere with the transglycosylation reaction, moenomycins are the only compounds known to date that directly interact with the transglycosylases rather than bind to their substrates [3]. The moenomycins therefore represent an interesting template for the design of new antibiotic drugs [3,7,8,13,14], which are highly desired because of the problem of bacterial resistance [14 -18]. Now, five major components of the Flavomycin complex have been structurally characterized, namely moenomycin A [19 -21], moenomycin A 12 [22], moenomycin C 4 [23], moenomycin C 3 [23], and moenomycin C 1 [24].…”

“…The chemical structures of the five major components of the Flavomycin complex have been established by 13 C-NMR spectroscopy and fast-atom-bombardment (FAB)-mass spectrometry (MS) of the purified compounds [20 -24] and were later confirmed by 1 H-NMR spectroscopy [31]. Subramaniam-Niehaus et al [32] have used liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) to confirm the presence of these five compounds in the culture filtrate of S. ghanaensis.…”