Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
Xuhui Zheng
Department of Microbiology, New York University Grossman School of Medicine, 430 East 29th Street, New York, NY 10016, USA
Dora Čerina
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
Keenan A. Lacey
Department of Microbiology, New York University Grossman School of Medicine, 430 East 29th Street, New York, NY 10016, USA
Menghan Liu
Department of Microbiology, New York University Grossman School of Medicine, 430 East 29th Street, New York, NY 10016, USA
Daniel Humme
Department of Dermatology, Venerology and Allergology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
Christian Goosmann
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
Volker Brinkmann
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
C.J. Harbort
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany
Victor J. Torres
Department of Microbiology, New York University Grossman School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Corresponding author
Arturo Zychlinsky
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany; Corresponding author
Summary: The antimicrobial activity of histones was discovered in the 1940s, but their mechanism of action is not fully known. Here we show that methicillin-resistant Staphylococcus aureus (MRSA) is susceptible to histone H1 (H1), even in the presence of divalent cations and serum. Through selective evolution and a genome-wide screen of a transposon library, as well as physiological and pharmacological experiments, we elucidated how H1 kills MRSA. We show that H1 first binds to wall teichoic acids with high affinity. Once bound, H1 requires a potentiated membrane and a metabolically active bacterium to permeabilize the membrane and enter the cell. Upon entry, H1 accumulates intracellularly, in close association with the bacterial DNA. Of note, anti-H1 antibodies inhibit neutrophil extracellular trap killing of MRSA. Moreover, H1 colocalizes with bacterial DNA in abscess samples of MRSA-infected patients, suggesting a role for H1 in combating MRSA in vivo.
