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De novo guanine biosynthesis is an evolutionarily conserved pathway that creates sufficient nucleotides to support DNA replication, transcription, and translation. Bacteria can also salvage nutrients from the environment to supplement thede novo pathway, but the relative importance of either pathway duringStaphylococcus aureus infection is not known. InS. aureus , genes important for bothde novo and salvage pathways are regulated by a guanine riboswitch. Bacterial riboswitches have attracted attention as a novel class of antibacterial drug targets because they have high affinity for small molecules, are absent in humans, and regulate the expression of multiple genes, including those essential for cell viability. Genetic and biophysical methods confirm the existence of a bona fide guanine riboswitch upstream of an operon encoding xanthine phosphoribosyltransferase (xpt ), xanthine permease (pbuX ), inosine-5′-monophosphate dehydrogenase (guaB ), and GMP synthetase (guaA ) that represses the expression of these genes in response to guanine. We found thatS. aureus guaB andguaA are also transcribed independently of riboswitch control by alternative promoter elements. Deletion ofxpt-pbuX-guaB-guaA genes resulted in guanine auxotrophy, failure to grow in human serum, profound abnormalities in cell morphology, and avirulence in mouse infection models, whereas deletion of the purine salvage genesxpt-pbuX had none of these effects. Disruption ofguaB orguaA recapitulates thexpt-pbuX-guaB-guaA deletionin vivo . In total, the data demonstrate that targeting the guanine riboswitch alone is insufficient to treatS. aureus infections but that inhibition ofguaA orguaB could have therapeutic utility.IMPORTANCE De novo guanine biosynthesis and purine salvage genes were reported to be regulated by a guanine riboswitch inStaphylococcus aureus . We demonstrate here that this is not true, because alternative promoter elements that uncouple thede novo pathway from riboswitch regulation were identified. We found that in animal models of infection, the purine salvage pathway is insufficient forS. aureus survival in the absence ofde novo guanine biosynthesis. These data suggest targeting thede novo guanine biosynthesis pathway may have therapeutic utility in the treatment ofS. aureus infections.

journal of bacteriology

<i>De Novo</i> Guanine Biosynthesis but Not the Riboswitch-Regulated Purine Salvage Pathway Is Required for Staphylococcus aureus Infection <i>In Vivo</i>

De Novo Guanine Biosynthesis but Not the Riboswitch-Regulated Purine Salvage Pathway Is Required for Staphylococcus aureus Infection In Vivo