The acquisition and metabolism of heme is of critical importance to the pathogenesis of Staphylococcus aureus, a bacterium of significant concern to public health. S. aureus acquires heme from its host to provide iron for cellular processes and to drive pathogenesis, but in high concentrations heme is toxic. The bacterium regulates heme levels through the HssRS two component system which upon activation induces expression of the efflux pump HrtAB which then alleviates heme toxicity. The mechanism by which HssRS senses heme is not well understood. A high throughput screen for activators of the HssRS system yielded the lead compounds, '8882 and '3981. We have demonstrated that '8882 activates heme sensing by increasing intracellular heme concentration and is dependent on the heme biosynthesis pathway while '3981 does not cause heme accumulation or require intact heme biosynthesis. Using a medicinal chemistry approach, we have determined structure activity relationships for both molecules and developed photoaffinity probes with clickable handles to identify the proteins with which these molecules interact. Coupled with parallel genetic approaches, we hope to elucidate the mechanism of HssRS heme sensing and understand the interplay and regulation of exogenous heme acquisition and endogenous heme biosynthesis.

Probing heme biosynthesis and homeostasis in <i>Staphylococcus aureus</i>

248th National Meeting (2014)

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Probing heme biosynthesis and homeostasis in Staphylococcus aureus