Abstract
ABSTRACTAcquisition of numerous virulence determinants affords Staphylococcus aureus greater pathogenicity than other skin-colonizing staphylococci in humans. Additionally, the metabolic adaptation of S. aureus to nonrespiratory conditions encountered during infection (e.g., hypoxia, nitric oxide, iron chelation) has been implicated as contributing to S. aureus virulence. Specifically, S. aureus has been shown to ferment glycolytic substrates in nonrespiratory environments encountered within the host. Here, we show that S. aureus has acquired unique carbohydrate transporters that facilitate the maximal uptake of host sugars and serve to support nonrespiratory growth in inflamed tissue. The carbohydrate substrates of 11 S. aureus transporters were identified, and at least four of their genes encode S. aureus glucose transporters (glcA, glcB, glcC, and glcU). Moreover, two transporter genes (glcA and glcC) are unique to S. aureus and contribute disproportionately to the nonrespiratory growth of S. aureus on glucose. Targeted inactivation of sugar transporters reduced glucose uptake and attenuated S. aureus in a murine model of skin and soft tissue infections. These data expand the evidence for metabolic adaptation of S. aureus to invasive infection and demonstrate the specific requirement for the fermentation of glucose over all other available carbohydrates. Ultimately, acquisition of foreign genes allows S. aureus to adopt a metabolic strategy resembling that of infiltrating host immune cells: high glycolytic flux coupled to lactate excretion.
Highlights
Acquisition of numerous virulence determinants affords Staphylococcus aureus greater pathogenicity than other skin-colonizing staphylococci in humans
To test whether this enhanced growth behavior occurs under other nonrespiratory conditions, we compared the anaerobic growth of S. aureus strains COL and LAC to that of S. epidermidis RP62A, S. haemolyticus ATCC 29970, and S. saprophyticus ATCC 15305 in a rich medium
Both strains of S. aureus exhibited better growth than the other Staphylococcus species, as evidenced by significantly greater growth rates and terminal optical densities (ODs) (Fig. 1A and B)
Summary
Acquisition of numerous virulence determinants affords Staphylococcus aureus greater pathogenicity than other skin-colonizing staphylococci in humans. Many other species of staphylococci (e.g., S. epidermidis, S. haemolyticus, S. saprophyticus, etc.) colonize human skin but cause disease far less frequently and with less severity than S. aureus [6] This difference has been extensively studied and is generally attributed to the combined presence of numerous unique virulence factors in the S. aureus genome, such as toxins, adhesins, antiphagocytic factors, and protein A [7,8,9]. The lack of abundant iron during infection limits respiration and necessitates high glycolytic flux coupled to lactate excretion [15, 17] This metabolic strategy, which is similar to that of activated immune cells, allows for the generation of ATP in a redox-balanced, respirationindependent manner. PTS-dependent transport is functionally linked to the transcriptional regulation of cellular metabolism via carbon catabolite repression (mediated by CcpA in Gram-positive bacteria), which further contributes to overall metabolic efficiency
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