A redundant isoprenoid biosynthetic pathway supports <i>Staphylococcus aureus</i> metabolic versatility

Isoprenoid synthesis is an essential process that is presumed to be initiated by the prenyl diphosphate synthase (PDS), IspA. However, our understanding of this pathway is incomplete considering that <i>ispA</i> mutants have been described in several bacterial species, leaving the mechanism for isoprenoid synthesis initiation uncertain in these genetic backgrounds. Using the opportunistic pathogen <i>Staphylococcus aureus</i>, we demonstrate that a second PDS, HepT, supports the production of isoprenoid-dependent molecules in the absence of IspA. Importantly, we show that mutants deficient for either IspA or HepT display colonization defects in a murine model of systemic infection. Furthermore, the simultaneous mutation of <i>hepT</i> and <i>ispA</i> is tolerated in <i>S. aureus</i> and suggests the presence of a third PDS capable of initiating isoprenoid synthesis. This study establishes PDSs as viable targets for the treatment of <i>S. aureus</i> infections and provides novel insights into the redundant nature of isoprenoid synthesis in this pathogen.