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The ability of  Staphylococcus aureus  and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for manganese sensitizing  S .  aureus  to host-imposed manganese starvation. The current investigations were undertaken to elucidate how  S .  aureus  copes with the need to consume glucose when metal-limited by the host. A critical component of host defense is production of the manganese binding protein calprotectin.  S .  aureus  has two variants of phosphoglycerate mutase, one of which is manganese-dependent, GpmI, and another that is manganese-independent, GpmA. Leveraging the ability to impose metal starvation in culture utilizing calprotectin revealed that the loss of GpmA, but not GpmI, sensitized  S .  aureus  to manganese starvation. Metabolite feeding experiments revealed that the growth defect of GpmA when manganese-starved was due to a defect in glycolysis and not gluconeogenesis. Loss of GpmA reduces the ability of  S .  aureus  to cause invasive disease in wild type mice. However, GpmA was dispensable in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of  S .  aureus  to overcome manganese limitation during infection. Cumulatively, these observations suggest that expressing a metal-independent variant enables  S .  aureus  to consume glucose while mitigating the negative impact that glycolysis has on the cellular demand for manganese.  S .  aureus  is not the only bacterium that expresses manganese-dependent and -independent variants of phosphoglycerate mutase. Similar results were also observed in culture with  Salmonella enterica  serovar Typhimurium mutants lacking the metal-independent isozyme. These similar observations in both Gram-positive and Gram-negative pathogens suggest that expression of metal-independent glycolytic isozymes is a common strategy employed by bacteria to survive in metal-limited environments, such as the host.

Metal-independent variants of phosphoglycerate mutase promote resistance to nutritional immunity and retention of glycolysis during infection