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.

Australian Synchrotron ANSTO 800 Blackburn Road Clayton 3168 Victoria Australia

Biomedicine Discovery Institute Department of Microbiology Monash University Clayton 3800 Australia

Department of Biochemistry and Molecular Biology Monash University Clayton 3800 Australia

Department of Molecular and Translational Sciences Monash University Clayton 3800 Australia

Hudson Institute of Medical Research Clayton 3800 Victoria Australia

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague 6 CZ 166 10 Czech Republic

Katholieke Universiteit Leuven Rega Institute for Medical Research Leuven 3000 Belgium

The School of Chemistry and Molecular Biosciences The University of Queensland Brisbane 4072 Queensland Australia

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Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design