Staphylococcus aureus Redirects Central Metabolism to Increase Iron Availability

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Abstract
Staphylococcus aureus pathogenesis is significantly influenced by the iron status of the host. However, the regulatory impact of host iron sources on S. aureus gene expression remains unknown. In this study, we combine multivariable difference gel electrophoresis and mass spectrometry with multivariate statistical analyses to systematically cluster cellular protein response across distinct iron-exposure conditions. Quadruplicate samples were simultaneously analyzed for alterations in protein abundance and/or post-translational modification state in response to environmental (iron chelation, hemin treatment) or genetic (Δfur) alterations in bacterial iron exposure. We identified 120 proteins representing several coordinated biochemical pathways that are affected by changes in iron-exposure status. Highlighted in these experiments is the identification of the heme-regulated transport system (HrtAB), a novel transport system which plays a critical role in staphylococcal heme metabolism. Further, we show that regulated overproduction of acidic end-products brought on by iron starvation decreases local pH resulting in the release of iron from the host iron-sequestering protein transferrin. These findings reveal novel strategies used by S. aureus to acquire scarce nutrients in the hostile host environment and begin to define the iron and heme-dependent regulons of S. aureus. Virtually all bacterial pathogens require iron to successfully infect their human hosts. This presents a problem to invading bacteria because the majority of iron in humans is tightly bound by iron-binding proteins. To counteract this host defense, bacterial pathogens have developed elaborate mechanisms to acquire nutrient iron during infection. To gain insight into how the amount of available iron impacts the human pathogen Staphylococcus aureus, the authors identified proteins that increase or decrease abundance upon alterations in iron status. The authors found that under conditions of iron starvation, the Fur regulatory protein of S. aureus coordinates a redirection of the central metabolic pathways causing the bacteria to produce large amounts of acidic end-products. The accumulation of these acidic end-products facilitates the release of iron from host iron-binding proteins, in effect increasing the availability of this precious nutrient source. These findings provide a mechanistic explanation for how S. aureus alters its local microenvironment during infection to increase the availability of nutrient iron. Based on the well-established role for bacterial iron acquisition during pathogenesis, systems involved in iron acquisition represent excellent potential therapeutic targets against bacterial infection.

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