Nicotinate phosphoribosyltransferase: a novel antiinfective target? (585.11)

Abstract

The essential coenzyme nicotinamide adenine dinucleotide (NAD) plays important roles in metabolic reactions and cell regulation in all organisms. Enzymes involved in NAD cofactor synthesis are promising targets for antiinfective drug development. So far efforts in this direction have been focused on targeting downstream conserved enzymes, common to both de novo and salvage pathways. Our comparative genome analysis indicated that a wide range of pathogens, ranging from gram positive streptococci and staphylococci to malarial and schistosoma parasites, lack the gene set responsible for NAD de novo biosynthesis. This means they are obligate vitamin B3 auxotrophs, and depend on scavenging nicotinate (or nicotinamide) from their host for NAD synthesis. The key enzyme for such essential salvage route is Nicotinate Phosphoribosyl Transferase (NaPRT) which catalyzes the transfer of a phosphoribosyl moiety on the nicotinate, yielding Nicotinate Mononucleotide (NaMN). In this work we started to explore the potential of NaPRT enzyme as a novel antiinfective drug target. We carried out a biochemical characterization of the enzyme from Staphylococcus aureus and Streptococcus pyogenes, followed by a site-directed mutagenesis analysis of key residues, and identified small molecule inhibitors by structure-based in silico screening. Grant Funding Source: This work was supported by the “Montalcini International Programme” to LS