Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus

Abstract

Staphylococcus aureus is a significant infectious threat to global public health. Acquisition or synthesis of heme is required for S. aureus to capture energy through respiration, but an excess of this critical cofactor is toxic to bacteria. S. aureus employs the heme sensor system (HssRS) to overcome heme toxicity; however, the mechanism of heme sensing is not defined. Here, we describe the identification of a small molecule activator of HssRS that induces endogenous heme biosynthesis by perturbing central metabolism. This molecule is toxic to fermenting S. aureus , including clinically relevant small colony variants. The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. Not only is this small molecule a powerful tool for studying bacterial heme biosynthesis and central metabolism; it also establishes targeting of fermentation as a viable antibacterial strategy.

A Small-Molecule Inhibitor of Iron-Sulfur Cluster Assembly Uncovers a Link between Virulence Regulation and Metabolism in Staphylococcus aureus

“…Previously, we identified small-molecule VU0038882 (’882), which activates endogenous heme biosynthesis in S. aureus while toxic to S. aureus grown anaerobically (Mike et al, 2013). ’882 exhibits a half maximal inhibitory concentration (IC 50 ) of ~162 μM to aerobic S. aureus and an IC 50 of ~5 μM to anaerobic S. aureus (Mike et al, 2013).…”

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

“…In addition to activating HssRS, treatment with '882 induces toxicity to bacteria undergoing fermentation by impacting iron-sulfur cluster biogenesis (11,14). Through a medicinal chemistry approach, the HssRS-activating properties of '882 were decoupled from its toxicity, suggesting two distinct cellular targets for this small molecule (11,14,15). Before this investigation, the mechanism by which '882 activates heme biosynthesis to trigger HssRS had not been uncovered.…”

“…Upon activation, HssRS induces the expression of the heme-regulated transporter (HrtAB) to alleviate heme toxicity (11)(12)(13). HssRS activation is triggered by massive accumulation of heme in '882-exposed bacteria (11). In addition to activating HssRS, treatment with '882 induces toxicity to bacteria undergoing fermentation by impacting iron-sulfur cluster biogenesis (11,14).…”

“…1B). Upon activation, HssRS induces the expression of the heme-regulated transporter (HrtAB) to alleviate heme toxicity (11)(12)(13). HssRS activation is triggered by massive accumulation of heme in '882-exposed bacteria (11).…”

“…Small-molecule VU0038882 ('882) was previously identified in a screen for activators of the S. aureus heme-sensing system twocomponent system (HssRS) (11)(12)(13) (Fig. 1B).…”