Physical Mechanisms of Bacterial Killing by Histones
Antibiotic resistance is a global epidemic, becoming increasingly pressing due to its rapid spread. There is thus a critical need to develop new therapeutic approaches. In addition to searching for new antibiotics, looking into existing mechanisms of natu
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Physical Mechanisms of Bacterial Killing by Histones Tory Doolin, Steven Gross, and Albert Siryaporn
Abstract
Antibiotic resistance is a global epidemic, becoming increasingly pressing due to its rapid spread. There is thus a critical need to develop new therapeutic approaches. In addition to searching for new antibiotics, looking into existing mechanisms of natural host defense may enable researchers to improve existing defense mechanisms, and to develop effective, synthetic drugs guided by natural principles. Histones, primarily known for their role in condensing mammalian DNA, are antimicrobial and share biochemical similarities with antimicrobial peptides (AMPs); however, the mechanism by which histones kill bacteria is largely unknown. Both AMPs and histones are T. Doolin Department of Developmental and Cell Biology, UC Irvine, Irvine, CA, USA
similar in size, cationic, contain a high proportion of hydrophobic amino acids, and possess the ability to form alpha helices. AMPs, which mostly kill bacteria through permeabilization or disruption of the biological membrane, have recently garnered significant attention for playing a key role in host defenses. This chapter outlines the structure and function of histone proteins as they compare to AMPs and provides an overview of their role in innate immune responses, especially regarding the action of specific histones against microorganisms and their potential mechanism of action against microbial pathogens. Keywords
Mammalian histones · Antimicrobial peptides · LL-37 · Neutrophil extracellular traps · Antimicrobial synergy · Host-microbe interactions
S. Gross () Department of Developmental and Cell Biology, UC Irvine, Irvine, CA, USA Department of Physics & Astronomy, UC Irvine, Irvine, CA, USA e-mail: [email protected]
Abbreviations
A. Siryaporn () Department of Physics & Astronomy, UC Irvine, Irvine, CA, USA
H1 H2A H2B H3 H4 AMP
Department of Molecular Biology & Biochemistry, UC Irvine, Irvine, CA, USA e-mail: [email protected]
Histone H1 Histone H2A Histone H2B Histone H3 Histone H4 Antimicrobial Peptide
© Springer Nature Switzerland AG 2020 G. Duménil, S. van Teeffelen (eds.), Physical Microbiology, Advances in Experimental Medicine and Biology 1267, https://doi.org/10.1007/978-3-030-46886-6_7
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NETs LDs LPS LTA PAD4 MIC CRAMP NMDA
7.1
T. Doolin et al.
Neutrophil Extracellular Traps Lipid Droplets Lipopolysaccharide Lipoteichoic acid Peptidyl arginine deiminase, type IV Minimum inhibitory concentration Cathelin-related antimicrobial peptide N-methyl-D-aspartate
Introduction
In 1922, Alexander Fleming discovered lysozyme from nasal mucus (Fleming 1922). This was the first human antimicrobial protein to be reported; however, the discovery of penicillin in 1928 (Fleming 1980) overshadowed this finding, and ushered the world into the “Golden Age” of antibiotics. Recently, the rise of antibiotic resistance, combined with the stagnation in discovering new, viable antimicrobial agents, has sparked renewed interest in natural host defenses. The anti
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