Helicobacter pylori Xanthine–Guanine–Hypoxanthine PhosphoribosyltransferaseA Putative Target for Drug Discovery against Gastrointestinal Tract Infections

Helicobacter pylori (Hp) is a human
pathogen that lives in the gastric mucosa of approximately 50% of
the world’s population causing gastritis, peptic ulcers, and
gastric cancer. An increase in resistance to current drugs has sparked
the search for new Hp drug targets and therapeutics. One target is
the disruption of nucleic acid production, which can be achieved by
impeding the synthesis of 6-oxopurine nucleoside monophosphates, the
precursors of DNA and RNA. These metabolites are synthesized by Hp
xanthine–guanine–hypoxanthine phosphoribosyltransferase
(XGHPRT). Here, nucleoside phosphonates have been evaluated, which
inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest
the growth of Hp at a concentration of 50 μM in cell-based assays.
The kinetic properties of HpXGHPRT have been determined together with
its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing
a basis for new antibiotic development.