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

Doolin, Tory; Amir, Henry M.; Duong, Leora; Rosenzweig, Rachel; Urban, Lauren A.; Bosch, Marta; Pol, Albert; Gross, Steven P.; Siryaporn, Albert

doi:10.1038/s41467-020-17699-z

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

Journal Article · Tue Aug 04 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-17699-z· OSTI ID:1817134

Doolin, Tory ^[1]; ^[2]; Duong, Leora ^[3]; ^[4]; Urban, Lauren A. ^[5]; Bosch, Marta ^[6]; ^[7]; Gross, Steven P. ^[8]; ^[9]

Univ. of California, Irvine, CA (United States). Dept. of Developmental and Cell Biology; OSTI
Univ. of California, Irvine, CA (United States). Dept. of Physics and Astronomy
Univ. of California, Irvine, CA (United States). Dept. of Molecular Biology & Biochemistry
Univ. of California, Irvine, CA (United States). Dept. of Materials Sciences and Engineering
Univ. of California, Irvine, CA (United States). Dept. of Microbiology and Molecular Genetics
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona (Spain). Cell Compartments and Signaling Group; Universitat de Barcelona (Spain). Faculty of Medicine. Dept. of Biomedical Sciences
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona (Spain). Cell Compartments and Signaling Group; Universitat de Barcelona (Spain). Faculty of Medicine. Dept. of Biomedical Sciences; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona (Spain)
Univ. of California, Irvine, CA (United States). Dept. of Developmental and Cell Biology; Univ. of California, Irvine, CA (United States). Dept. of Physics and Astronomy
Univ. of California, Irvine, CA (United States). Dept. of Developmental and Cell Biology; Univ. of California, Irvine, CA (United States). Dept. of Molecular Biology & Biochemistry

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.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of California, Irvine, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1817134

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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