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Small protein biologics called centyrins can be engineered to combat the toxicity caused by systemic Staphylococcus aureus infection. Circumventing Staphylococcus aureus subversion: Staphylococcus aureus subverts the host immune system with various mechanisms, including the cytolytic leukocidins. Chan et al. modified a protein scaffold to generate centryins, which bind S. aureus leukocidins in vitro and can protect human cells from leukocidin-mediated lysis. Further modification to extend centryin half-life in circulation led to antibacterial protection in various mouse models. These centryins could one day be used to prevent or possibly treat S. aureus infections in people. A key aspect underlying the severity of infections caused by Staphylococcus aureus is the abundance of virulence factors that the pathogen uses to thwart critical components of the human immune response. One such mechanism involves the destruction of host immune cells by cytolytic toxins secreted by S. aureus, including five bicomponent leukocidins: PVL, HlgAB, HlgCB, LukED, and LukAB. Purified leukocidins can lyse immune cells ex vivo, and systemic injections of purified LukED or HlgAB can acutely kill mice. Here, we describe the generation and characterization of centyrins that bind S. aureus leukocidins with high affinity and protect primary human immune cells from toxin-mediated cytolysis. Centyrins are small protein scaffolds derived from the fibronectin type III–binding domain of the human protein tenascin-C. Although centyrins are potent in tissue culture assays, their short serum half-lives limit their efficacies in vivo. By extending the serum half-lives of centyrins through their fusion to an albumin-binding consensus domain, we demonstrate the in vivo efficacy of these biologics in a murine intoxication model and in models of both prophylactic and therapeutic treatment of live S. aureus systemic infections. These biologics that target S. aureus virulence factors have potential for treating and preventing serious staphylococcal infections. [ABSTRACT FROM AUTHOR]