Mannose-inhibitable

Recently a form of type 1 fimbriae has been described which, in addition to binding carbohydrates, interacts also with non-glycosylated regions of proteins in a mannose-inhibitable manner [51]. It is not clear whether this interaction occurs via the carbohydrate binding site proper and how it is inhibited by mannose. The difference between the two... 

Thus, in the first group of bacteria, GDP-D-mannose inhibits its own synthesis by a simple feed-back inhibition. A similar mechanism is also operative in the second group, where GDP-L-fucose inhibits both GDP-D-mannose pyrophosphorylase and GDP-D-mannose oxi-doreductase. In the third group, where both sugar nucleotides are needed for polysaccharide synthesis, their biosynthesis is individually controlled, so that imbalance in the supply of these two sugars will not occur. 

Amphomycin inhibits bacterial ceU wall synthesis at the translocase step by binding to the large isoprenoid Hpid called undecaprenylphosphate (173,174). In eukaryotes, in a similar manner, amphomycin binds to the large isoprenoid Hpid called doHcholphosphate thus blocking the transfer of mannose from its uridinediphosphate derivative to this Hpid (173—177). Amphomycin has been patented for use as a feed additive (178). 

Preliminary biological data on this series of mannosylated clusters indicated interesting potency in the inhibition of agglutination of E. coli x7122 by baker s yeast, with approximately a hundred times improved efficiency than those obtained with monomeric D-mannose. 

Finally, the clusters were tested as inhibitors of hemagglutination of pig and rabbit erythrocytes by type-1 piliated UTI89 clinical isolate E. coli. The inhibition titer (IT), that is, the lowest concentration of the inhibitor at which no agglutination occurs, showed tetramer 51 to be the best inhibitor of hemagglutination, with an IT of about 3 fiM, or a factor of 6000 as compared to its affinity, and corresponding to 1000-fold better inhibition than that induced by D-mannose. Overall, tetravalent cluster 51 was the best noncovalent cross-linker of Con A and the best ligand known to E. coli K12 FimH. 

Binding affinities of the new flexible synthetic glycocluster toward type-1-piliated E. coli were evaluated by HAI and bladder-binding assay (BBA). The results indicated that, with an inhibition of bacterial bladder-cell binding at 12 nM ( 6000- and 64-fold lower than mannose and 59, respectively), the tetravalent compound 60 is currently one of the most promising antiadhesive drugs under development for the treatment of urinary tract infections. 

E. A. L. Biessen, F. Noorman, M. E. van Teijlingen, J. Kuiper, M. Barrett-Bergshoeff, M. K. Bijsterbosch, D. C. Rijken, and T. J. C. Van Berkel, Lysine-based cluster mannosides that inhibit ligand binding to the human mannose receptor at nanomolar concentration, J. Biol. Chem., 271 (1996) 28024—28030. 

Figure 14.8 (A) Screening of a glycopeptide library using a fluorescent-labeled lectin and ligands bound to PEGA beads. The acbve compounds are analysed by mass spectrometry. (B) FITC-labeled lectin binding to resin bound mannose could be inhibited by soluble glycopeptides obtained from library screen. Percent inhibition was quantified by recording of lectin fluorescence. Only every second well of the microtiter plate was used and nonfluorescent beads indicated good inhibitors.44...

---