Inhibitors for Bacterial Cell-Wall Recycling

Gram-negative bacteria have evolved an elaborate process
for the
recycling of their cell wall, which is initiated in the periplasmic
space by the action of lytic transglycosylases. The product of this
reaction, β-d-N-acetylglucosamine-(1→4)-1,6-anhydro-β-d-N-acetylmuramyl-l-Ala-γ-d-Glu-meso-DAP-d-Ala-d-Ala
(compound 1), is internalized to begin the recycling
events within the cytoplasm. The first step in the cytoplasmic recycling
is catalyzed by the NagZ glycosylase, which cleaves in a hydrolytic
reaction the N-acetylglucosamine glycosidic bond
of metabolite 1. The reactions catalyzed by both the
lytic glycosylases and NagZ are believed to involve oxocarbenium transition
species. We describe herein the synthesis and evaluation of four iminosaccharides
as possible mimetics of the oxocarbenium species, and we disclose
one as a potent (compound 3, Ki = 300 ± 15 nM) competitive inhibitor of NagZ.