Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography
Abstract The abuse of antibiotics has led to the emergence of multidrug-resistant microbial pathogens, presenting a pressing challenge in global healthcare. Membrane-disrupting antimicrobial peptides (AMPs) combat so-called superbugs via mechanisms different than conventional antibiotics and have go...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Nature Portfolio
2023-09-01
|
Series: | Nature Communications |
Online Access: | https://doi.org/10.1038/s41467-023-41156-2 |
_version_ | 1797557946680344576 |
---|---|
author | Eric H.-L. Chen Chun-Hsiung Wang Yi-Ting Liao Feng-Yueh Chan Yui Kanaoka Takayuki Uchihashi Koichi Kato Longsheng Lai Yi-Wei Chang Meng-Chiao Ho Rita P.-Y. Chen |
author_facet | Eric H.-L. Chen Chun-Hsiung Wang Yi-Ting Liao Feng-Yueh Chan Yui Kanaoka Takayuki Uchihashi Koichi Kato Longsheng Lai Yi-Wei Chang Meng-Chiao Ho Rita P.-Y. Chen |
author_sort | Eric H.-L. Chen |
collection | DOAJ |
description | Abstract The abuse of antibiotics has led to the emergence of multidrug-resistant microbial pathogens, presenting a pressing challenge in global healthcare. Membrane-disrupting antimicrobial peptides (AMPs) combat so-called superbugs via mechanisms different than conventional antibiotics and have good application prospects in medicine, agriculture, and the food industry. However, the mechanism-of-action of AMPs has not been fully characterized at the cellular level due to a lack of high-resolution imaging technologies that can capture cellular-membrane disruption events in the hydrated state. Previously, we reported PepD2M, a de novo-designed AMP with potent and wide-spectrum bactericidal and fungicidal activity. In this study, we use cryo-electron tomography (cryo-ET) and high-speed atomic force microscopy (HS-AFM) to directly visualize the pepD2M-induced disruption of the outer and inner membranes of the Gram-negative bacterium Escherichia coli, and compared with a well-known pore-forming peptide, melittin. Our high-resolution cryo-ET images reveal how pepD2M disrupts the E. coli membrane using a carpet/detergent-like mechanism. Our studies reveal the direct membrane-disrupting consequence of AMPs on the bacterial membrane by cryo-ET, and this information provides critical insights into the mechanisms of this class of antimicrobial agents. |
first_indexed | 2024-03-10T17:24:25Z |
format | Article |
id | doaj.art-77ddcb9b73dc4a1a9df003d2347f0c69 |
institution | Directory Open Access Journal |
issn | 2041-1723 |
language | English |
last_indexed | 2024-03-10T17:24:25Z |
publishDate | 2023-09-01 |
publisher | Nature Portfolio |
record_format | Article |
series | Nature Communications |
spelling | doaj.art-77ddcb9b73dc4a1a9df003d2347f0c692023-11-20T10:14:18ZengNature PortfolioNature Communications2041-17232023-09-0114111210.1038/s41467-023-41156-2Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomographyEric H.-L. Chen0Chun-Hsiung Wang1Yi-Ting Liao2Feng-Yueh Chan3Yui Kanaoka4Takayuki Uchihashi5Koichi Kato6Longsheng Lai7Yi-Wei Chang8Meng-Chiao Ho9Rita P.-Y. Chen10Institute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaDepartment of Physics, Nagoya UniversityDepartment of Physics, Nagoya UniversityDepartment of Physics, Nagoya UniversityExploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural SciencesDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaAbstract The abuse of antibiotics has led to the emergence of multidrug-resistant microbial pathogens, presenting a pressing challenge in global healthcare. Membrane-disrupting antimicrobial peptides (AMPs) combat so-called superbugs via mechanisms different than conventional antibiotics and have good application prospects in medicine, agriculture, and the food industry. However, the mechanism-of-action of AMPs has not been fully characterized at the cellular level due to a lack of high-resolution imaging technologies that can capture cellular-membrane disruption events in the hydrated state. Previously, we reported PepD2M, a de novo-designed AMP with potent and wide-spectrum bactericidal and fungicidal activity. In this study, we use cryo-electron tomography (cryo-ET) and high-speed atomic force microscopy (HS-AFM) to directly visualize the pepD2M-induced disruption of the outer and inner membranes of the Gram-negative bacterium Escherichia coli, and compared with a well-known pore-forming peptide, melittin. Our high-resolution cryo-ET images reveal how pepD2M disrupts the E. coli membrane using a carpet/detergent-like mechanism. Our studies reveal the direct membrane-disrupting consequence of AMPs on the bacterial membrane by cryo-ET, and this information provides critical insights into the mechanisms of this class of antimicrobial agents.https://doi.org/10.1038/s41467-023-41156-2 |
spellingShingle | Eric H.-L. Chen Chun-Hsiung Wang Yi-Ting Liao Feng-Yueh Chan Yui Kanaoka Takayuki Uchihashi Koichi Kato Longsheng Lai Yi-Wei Chang Meng-Chiao Ho Rita P.-Y. Chen Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography Nature Communications |
title | Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography |
title_full | Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography |
title_fullStr | Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography |
title_full_unstemmed | Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography |
title_short | Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography |
title_sort | visualizing the membrane disruption action of antimicrobial peptides by cryo electron tomography |
url | https://doi.org/10.1038/s41467-023-41156-2 |
work_keys_str_mv | AT erichlchen visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT chunhsiungwang visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT yitingliao visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT fengyuehchan visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT yuikanaoka visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT takayukiuchihashi visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT koichikato visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT longshenglai visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT yiweichang visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT mengchiaoho visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography AT ritapychen visualizingthemembranedisruptionactionofantimicrobialpeptidesbycryoelectrontomography |