Co-translational protein aggregation and ribosome stalling as a broad-spectrum antibacterial mechanism

Laleh Khodaparast, Ladan Khodaparast, Ramon Duran-Romaña, Guiqin Wu, Bert Houben, Wouter Duverger, Matthias Vleeschouwer, Katerina Konstantoulea, Fleur Nysen, Thomas Schalck, Daniel J. Curwen, Lisandra L. Martin, Sebastien Carpentier, Bernard Scorneaux, Jan Michiels, Joost Schymkowitz () and Frederic Rousseau ()
Additional contact information
Laleh Khodaparast: VIB Center for Brain and Disease Research
Ladan Khodaparast: VIB Center for Brain and Disease Research
Ramon Duran-Romaña: VIB Center for Brain and Disease Research
Guiqin Wu: VIB Center for Brain and Disease Research
Bert Houben: VIB Center for Brain and Disease Research
Wouter Duverger: VIB Center for Brain and Disease Research
Matthias Vleeschouwer: VIB Center for Brain and Disease Research
Katerina Konstantoulea: VIB Center for Brain and Disease Research
Fleur Nysen: VIB Center for Brain and Disease Research
Thomas Schalck: Centre of Microbial and Plant Genetics;KU Leuven
Daniel J. Curwen: Monash University
Lisandra L. Martin: Monash University
Sebastien Carpentier: KULeuven
Bernard Scorneaux: Aelin Therapeutics
Jan Michiels: Centre of Microbial and Plant Genetics;KU Leuven
Joost Schymkowitz: VIB Center for Brain and Disease Research
Frederic Rousseau: VIB Center for Brain and Disease Research

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Drug-resistant bacteria pose an urgent global health threat, necessitating the development of antibacterial compounds with novel modes of action. Protein biosynthesis accounts for up to half of the energy expenditure of bacterial cells, and consequently inhibiting the efficiency or fidelity of the bacterial ribosome is a major target of existing antibiotics. Here, we describe an alternative mode of action that affects the same process: allowing translation to proceed but causing co-translational aggregation of the nascent peptidic chain. We show that treatment with an aggregation-prone peptide induces formation of polar inclusion bodies and activates the SsrA ribosome rescue pathway in bacteria. The inclusion bodies contain ribosomal proteins and ribosome hibernation factors, as well as mRNAs and cognate nascent chains of many proteins in amyloid-like structures, with a bias for membrane proteins with a fold rich in long-range beta-sheet interactions. The peptide is bactericidal against a wide range of pathogenic bacteria in planktonic growth and in biofilms, and reduces bacterial loads in mouse models of Escherichia coli and Acinetobacter baumannii infections. Our results indicate that disrupting protein homeostasis via co-translational aggregation constitutes a promising strategy for development of broad-spectrum antibacterials.

Date: 2025
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DOI: 10.1038/s41467-025-56873-z

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