Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria

Inhibition of the biosynthesis of bacterial heptoses
opens novel
perspectives for antimicrobial therapies. The enzyme GmhA responsible
for the first committed biosynthetic step catalyzes the conversion
of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors
a Zn2+ ion in the active site. A series of phosphoryl-
and phosphonyl-substituted derivatives featuring a hydroxamate moiety
were designed and prepared from suitably protected ribose or hexose
derivatives. High-resolution crystal structures of GmhA complexed
to two N-formyl hydroxamate inhibitors confirmed
the binding interactions to a central Zn2+ ion coordination
site. Some of these compounds were found to be nanomolar inhibitors
of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity
of their own, they demonstrated in vitro lipopolysaccharide heptosylation
inhibition in Enterobacteriaceae as
well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the
way for a novel treatment of Gram-negative infections.