Fermentative growth decreases the iron demand of Staphylococcus aureus

Iron (Fe) is an essential nutrient for S. aureus survivability and pathogenesis, but excess Fe can catalyze the formation of toxic oxygen radicals, emphasizing the importance of maintaining proper Fe homeostasis. The essentiality of Fe for bacteria is exploited by host immunity strategies, which employ metal-binding proteins to decrease the availability of metal ions such as Fe. S. aureus responds to Fe limitation using the ferric uptake regulator (Fur) and the Fur protein antagonist (Fpa). During Fe-replete conditions, Fur functions as a transcriptional repressor of target genes. Upon Fe deprivation, Fur repression is relieved with the aid of Fpa, allowing for the increased expression of Fur-regulated genes such as iron uptake systems. We demonstrate that fur inactivation is required during Fe-limited growth and is independent of the described high-affinity Fe uptake systems. Using transcriptomic and metabolomic analyses, we demonstrate that fur inactivation or Fe limitation triggers a decrease in respiration and an increase in fermentation. Triggering fermentative growth allows S. aureus to cope with Fe limitation by having a metabolism less reliant on Fe but allowing for redox balance. Our work provides insight into how S. aureus adapts to iron limitation; a common stress encountered during infection.