Staphylococcus aureus infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which are highly abundant in eukaryotes and encountered by S. aureus at the host-pathogen interface. Arachidonic acid (AA) is one of the most abundant polyunsaturated fatty acids in vertebrates and is released in large amounts during the oxidative burst. Most of the released AA is converted to bioactive signaling molecules, but, independently of its role in inflammatory signaling, AA is toxic to S. aureus Here, we report that AA kills S. aureus through a lipid peroxidation mechanism whereby AA is oxidized to reactive electrophiles that modify S. aureus macromolecules, eliciting toxicity. This process is rescued by cotreatment with antioxidants as well as in a S. aureus strain genetically inactivated for lcpA (USA300 ΔlcpA mutant) that produces lower levels of reactive oxygen species. However, resistance to AA stress in the USA300 ΔlcpA mutant comes at a cost, making the mutant more susceptible to β-lactam antibiotics and attenuated for pathogenesis in a murine infection model compared to the parental methicillin-resistant S. aureus (MRSA) strain, indicating that resistance to AA toxicity increases susceptibility to other stressors encountered during infection. This report defines the mechanism by which AA is toxic to S. aureus and identifies lipid peroxidation as a pathway that can be modulated for the development of future therapeutics to treat S. aureus infections.IMPORTANCE Despite the ability of the human immune system to generate a plethora of molecules to control Staphylococcus aureus infections, S. aureus is among the pathogens with the greatest impact on human health. One class of host molecules toxic to S. aureus consists of polyunsaturated fatty acids. Here, we investigated the antibacterial properties of arachidonic acid, one of the most abundant polyunsaturated fatty acids in humans, and discovered that the mechanism of toxicity against S. aureus proceeds through lipid peroxidation. A better understanding of the molecular mechanisms by which the immune system kills S. aureus, and by which S. aureus avoids host killing, will enable the optimal design of therapeutics that complement the ability of the vertebrate immune response to eliminate S. aureus infections.

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