Mammalian histones facilitate antimicrobial synergy by disrupting the bacterial proton gradient and chromosome organization

Tory Doolin, Henry M. Amir, Leora Duong, Rachel Rosenzweig, Lauren A. Urban, Marta Bosch, Albert Pol, Steven P. Gross () and Albert Siryaporn ()
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Tory Doolin: UC Irvine
Henry M. Amir: UC Irvine
Leora Duong: UC Irvine
Rachel Rosenzweig: UC Irvine
Lauren A. Urban: UC Irvine
Marta Bosch: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Albert Pol: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Steven P. Gross: UC Irvine
Albert Siryaporn: UC Irvine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17699-z

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