First proposed as antimicrobial agents, histones were later recognized for their role in condensing chromosomes. Histone antimicrobial activity has been reported in innate immune responses. However, how histones kill bacteria has remained elusive. The co-localization of histones with antimicrobial peptides (AMPs) in immune cells suggests that histones may be part of a larger antimicrobial mechanism in vivo. Here we report that histone H2A enters E. coli and S. aureus through membrane pores formed by the AMPs LL-37 and magainin-2. H2A enhances AMP-induced pores, depolarizes the bacterial membrane potential, and impairs membrane recovery. Inside the cytoplasm, H2A reorganizes bacterial chromosomal DNA and inhibits global transcription. Whereas bacteria recover from the pore-forming effects of LL-37, the concomitant effects of H2A and LL-37 are irrecoverable. Their combination constitutes a positive feedback loop that exponentially amplifies their antimicrobial activities, causing antimicrobial synergy. More generally, treatment with H2A and the pore-forming antibiotic polymyxin B completely eradicates bacterial growth.

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Bacteria sense environmental stressors and activate responses to improve their survival in harsh growth conditions. Neutrophils respond to the presence of bacteria by producing oxidative antibacterial species including hypochlorous acid (HOCl). However, the extent that bacteria detect activated neutrophils or HOCl has not been known. Here, we report that the opportunistic bacterial pathogen Pseudomonas aeruginosa responds to activated neutrophils by activating the fro system, which regulates the expression of antioxidative factors. We show that this response is specific to HOCl and that other oxidative factors including H2O2, do not trigger a fro response. The fro system has been previously shown to detect flow that is present in host vasculature, such as in animal circulatory systems. Our data thus suggest a model in which fro serves as an early host detection system in P. aeruginosa that improves its survival against neutrophil-mediated defenses, which could promote colonization in human tissue and increase pathogenicity.