SYNTHESIS OF 1,5-ANHYDRO-D-GLYCERO-D-GLUCO-HEPTITOL DERIVATIVES AS POTENTIAL INHIBITORS OF BACTERIAL HEPTOSE BIOSYNTHETIC PATHWAYS

摘要

A threat to global health is presently associated with the increase of multidrug-resistant bacteria, for several of which common antibiotics are not effective anymore [1]. Novel approaches, such as the antivirulence concept, are therefore urgently needed to identify bacterial targets and to develop appropriate compounds with effective and specific modes of action. Various isomers of seven carbon sugars termed heptoses play crucial roles in gram negative bacteria. L-gr/ycero-D-manno-heptose has been found to link the inner and outer core region of lipopolysaccharide (LPS) which is located on the outer membrane of the cell envelope. The biosynthesis of heptoses and their nucleotide-activated forms has been elucidated in great detail. The first enzymatic steps are catalyzed by the sedoheptulose-7-phosphate isomerase GmhA and anomeric kinases HldE and HddA. Blocking these enzymes leads, for example, to deep rough type bacterial mutants of the Re chemotype with impaired barrier functions, which are rapidly cleared from serum by the immune system.