S. pyogenes is reliant on salvage of host pyridine precursors for NAD synthesis: implications for pathogenesis and antibacterial intervention

Abstract

The essential coenzyme nicotinamide adenine dinucleotide (NAD) plays important roles in metabolic reactions and cell regulation in all organisms. In bacteria, NAD metabolic subsystem has been recently investigated as a potential source of novel antibacterial targets. Our comparative genome analysis across nearly a thousand of bacterial species revealed that all Streptococcus pyogenes and pneumoniae strains – but not other Streptococci – have a disrupted de novo NAD biosynthesis making these bacterial pathogens completely reliant on the salvage of host pyridine precursors. Rather puzzlingly, while the two genes responsible for the conversion of L‐aspartate to quinolinate (nadB and nadA) are missing, the final gene of de novo pathway (nadC), encoding for quinolinate phosphoribosyltransferase, is present. Growth experiments confirmed that S. pyogenes is not able to grow on a chemically defined medium, while significant growth was observed when adding nicotinic acid, nicotinamide, and quinolinate. Biochemical characterization of NadC demostrated its activity in vitro, while the inability of our nadC knockout mutant to grow on quinolinate as opposed to wild type strain directly implicated NadC in quinolinate auxotrophy (in vivo). We propose that quinolinate auxotrophy might be linked with the pathogenesis of streptococcal diseases.