Visualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography

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 () and Rita P.-Y. Chen ()
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Eric H.-L. Chen: Academia Sinica
Chun-Hsiung Wang: Academia Sinica
Yi-Ting Liao: Academia Sinica
Feng-Yueh Chan: Nagoya University
Yui Kanaoka: Nagoya University
Takayuki Uchihashi: Nagoya University
Koichi Kato: Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences
Longsheng Lai: University of Pennsylvania
Yi-Wei Chang: University of Pennsylvania
Meng-Chiao Ho: Academia Sinica
Rita P.-Y. Chen: Academia Sinica

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41156-2

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