A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Staphylococcus aureus produces hospital- and community- acquired infections, with methicillin- resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil- based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase ( CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase ( SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol- lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro ( median inhibitory concentration similar to 100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor - based therapy against S. aureus.