Cytoplasmic condensation induced by membrane damage is associated with antibiotic lethality

Felix Wong, Jonathan M. Stokes, Bernardo Cervantes, Sider Penkov, Jens Friedrichs, Lars D. Renner () and James J. Collins ()
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Felix Wong: Massachusetts Institute of Technology
Jonathan M. Stokes: Massachusetts Institute of Technology
Bernardo Cervantes: Massachusetts Institute of Technology
Sider Penkov: Institute for Clinical Chemistry and Laboratory Medicine at the University Clinic and Medical Faculty of TU Dresden
Jens Friedrichs: Leibniz Institute of Polymer Research and the Max Bergmann Center of Biomaterials
Lars D. Renner: Leibniz Institute of Polymer Research and the Max Bergmann Center of Biomaterials
James J. Collins: Massachusetts Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Bactericidal antibiotics kill bacteria by perturbing various cellular targets and processes. Disruption of the primary antibiotic-binding partner induces a cascade of molecular events, leading to overproduction of reactive metabolic by-products. It remains unclear, however, how these molecular events contribute to bacterial cell death. Here, we take a single-cell physical biology approach to probe antibiotic function. We show that aminoglycosides and fluoroquinolones induce cytoplasmic condensation through membrane damage and subsequent outflow of cytoplasmic contents as part of their lethality. A quantitative model of membrane damage and cytoplasmic leakage indicates that a small number of nanometer-scale membrane defects in a single bacterium can give rise to the cellular-scale phenotype of cytoplasmic condensation. Furthermore, cytoplasmic condensation is associated with the accumulation of reactive metabolic by-products and lipid peroxidation, and pretreatment of cells with the antioxidant glutathione attenuates cytoplasmic condensation and cell death. Our work expands our understanding of the downstream molecular events that are associated with antibiotic lethality, revealing cytoplasmic condensation as a phenotypic feature of antibiotic-induced bacterial cell death.

Date: 2021
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DOI: 10.1038/s41467-021-22485-6

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