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Staphylococcus aureus is an important human pathogen causing a wide range of disease presentations. It harbors a vast array of virulence factors and drug-resistance determinants. All of these factors are coordinately regulated by a hand full of key transcriptional regulators. The regulation and expression of these factors are tightly intertwined with the metabolic state of the cell. Furthermore, alterations in central metabolism are also key to the ability of S. aureus to resist clearance by the host innate immune response, including nitric oxide (NO·) production. Given the fact that central metabolism directly influences virulence, drug resistance and immune tolerance in S. aureus, a better understanding of the metabolic capabilities of this pathogen is critical. This work highlights some of the major findings within the last five years surrounding S. aureus central metabolism, both organic and inorganic. These are also put in the context of the unique NO·-resistance associated with this pathogen as well as their contributions to virulence. The more we understand the intersection between central metabolism and virulence capabilities in S. aureus, the better the chances of developing novel therapeutics so desperately needed to treat this pathogen. [ABSTRACT FROM AUTHOR]

ABSTRACT Staphylococcus aureus is the most pathogenic member of the Staphylococcaceae. While it acquired an arsenal of canonical virulence determinants that mediate pathogenicity, it has also metabolically adapted to thrive at sites of inflammation. Notably, it has evolved to grow in the presence of nitric oxide (NO·). To this end, we note that the Rex regulon, composed of genes encoding dehydrogenases, metabolite transporters, and regulators, is much larger in S. aureus than other Staphylococcus species. Here, we demonstrate that this expanded Rex regulon is necessary and sufficient for NO· resistance. Preventing its expression results in NO· sensitivity, and the closely related species, Staphylococcus simiae, also possesses an expanded Rex regulon and exhibits NO· resistance. We hypothesize that the expanded Rex regulon initially evolved to provide efficient anaerobic metabolism but that S. aureus has co-opted this feature to thrive at sites of inflammation where respiration is limited. One distinguishing feature of the Rex regulon in S. aureus is that it contains the srrAB two-component system. Here, we show that Rex blocks the ability of SrrA to auto-induce the operon, thereby preventing maximal SrrAB expression. This results in NO·-responsive srrAB expression in S. aureus but not in other staphylococci. Consequently, higher expression of cytochromes and NO· detoxification are also observed in S. aureus alone, allowing for continued respiration at NO· concentrations beyond that of S. simiae. We therefore contend that the intersection of the Rex and SrrAB regulons represents an evolutionary event that allowed S. aureus to metabolically adapt to host inflammatory radicals during infection. IMPORTANCE Pathogens must evolve virulence potential to improve transmission to new hosts as well as evolve metabolically to thrive within their current host. Staphylococcus aureus has achieved both of these, and here, we show that one such metabolic adaptation was the expansion of the Rex regulon. First, it affords S. aureus with efficient respiration-independent growth critical to surviving the inflammatory environment replete with respiration-inhibiting immune radicals. Second, it includes the srrAB operon encoding a two-component system critical to maximizing respiratory capacity in the face of host nitric oxide (NO·), a potent respiratory inhibitor. This second facet is only apparent in S. aureus and not in other closely related species. Thus, evolutionarily, it must have occurred relatively recently. The intertwining of the Rex and SrrAB regulons represents an important evolutionary event that affords S. aureus the metabolic flexibility required to thrive within inflamed tissue and cause disease.

Staphylococcus aureus is an important human pathogen causing a wide range of disease presentations. It harbors a vast array of virulence factors and drug-resistance determinants. All of these factors are coordinately regulated by a hand full of key transcriptional regulators. The regulation and expression of these factors are tightly intertwined with the metabolic state of the cell. Furthermore, alterations in central metabolism are also key to the ability of S. aureus to resist clearance by the host innate immune response, including nitric oxide (NO·) production. Given the fact that central metabolism directly influences virulence, drug resistance and immune tolerance in S. aureus, a better understanding of the metabolic capabilities of this pathogen is critical. This work highlights some of the major findings within the last five years surrounding S. aureus central metabolism, both organic and inorganic. These are also put in the context of the unique NO·-resistance associated with this pathogen as well as their contributions to virulence. The more we understand the intersection between central metabolism and virulence capabilities in S. aureus, the better the chances of developing novel therapeutics so desperately needed to treat this pathogen., (Copyright © 2022 Elsevier Ltd All rights reserved.)

Staphylococcus aureus is the most pathogenic member of the Staphylococcaceae. While it acquired an arsenal of canonical virulence determinants that mediate pathogenicity, it has also metabolically adapted to thrive at sites of inflammation. Notably, it has evolved to grow in the presence of nitric oxide (NO·). To this end, we note that the Rex regulon, composed of genes encoding dehydrogenases, metabolite transporters, and regulators, is much larger in S. aureus than other Staphylococcus species. Here, we demonstrate that this expanded Rex regulon is necessary and sufficient for NO· resistance. Preventing its expression results in NO· sensitivity, and the closely related species, Staphylococcus simiae, also possesses an expanded Rex regulon and exhibits NO· resistance. We hypothesize that the expanded Rex regulon initially evolved to provide efficient anaerobic metabolism but that S. aureus has co-opted this feature to thrive at sites of inflammation where respiration is limited. One distinguishing feature of the Rex regulon in S. aureus is that it contains the srrAB two-component system. Here, we show that Rex blocks the ability of SrrA to auto-induce the operon, thereby preventing maximal SrrAB expression. This results in NO·-responsive srrAB expression in S. aureus but not in other staphylococci. Consequently, higher expression of cytochromes and NO· detoxification are also observed in S. aureus alone, allowing for continued respiration at NO· concentrations beyond that of S. simiae. We therefore contend that the intersection of the Rex and SrrAB regulons represents an evolutionary event that allowed S. aureus to metabolically adapt to host inflammatory radicals during infection. IMPORTANCE Pathogens must evolve virulence potential to improve transmission to new hosts as well as evolve metabolically to thrive within their current host. Staphylococcus aureus has achieved both of these, and here, we show that one such metabolic adaptation was the expansion of the Rex regulon. First, it affords S. aureus with efficient respiration-independent growth critical to surviving the inflammatory environment replete with respiration-inhibiting immune radicals. Second, it includes the srrAB operon encoding a two-component system critical to maximizing respiratory capacity in the face of host nitric oxide (NO·), a potent respiratory inhibitor. This second facet is only apparent in S. aureus and not in other closely related species. Thus, evolutionarily, it must have occurred relatively recently. The intertwining of the Rex and SrrAB regulons represents an important evolutionary event that affords S. aureus the metabolic flexibility required to thrive within inflamed tissue and cause disease.