Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides

Tomas Sneideris, Nadia A. Erkamp, Hannes Ausserwöger, Kadi L. Saar, Timothy J. Welsh, Daoyuan Qian, Kai Katsuya-Gaviria, Margaret L. L. Y. Johncock, Georg Krainer, Alexander Borodavka () and Tuomas P. J. Knowles ()
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Tomas Sneideris: University of Cambridge
Nadia A. Erkamp: University of Cambridge
Hannes Ausserwöger: University of Cambridge
Kadi L. Saar: University of Cambridge
Timothy J. Welsh: University of Cambridge
Daoyuan Qian: University of Cambridge
Kai Katsuya-Gaviria: University of Cambridge
Margaret L. L. Y. Johncock: University of Cambridge
Georg Krainer: University of Cambridge
Alexander Borodavka: University of Cambridge
Tuomas P. J. Knowles: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Antimicrobial peptides (AMPs), which combat bacterial infections by disrupting the bacterial cell membrane or interacting with intracellular targets, are naturally produced by a number of different organisms, and are increasingly also explored as therapeutics. However, the mechanisms by which AMPs act on intracellular targets are not well understood. Using machine learning-based sequence analysis, we identified a significant number of AMPs that have a strong tendency to form liquid-like condensates in the presence of nucleic acids through phase separation. We demonstrate that this phase separation propensity is linked to the effectiveness of the AMPs in inhibiting transcription and translation in vitro, as well as their ability to compact nucleic acids and form clusters with bacterial nucleic acids in bacterial cells. These results suggest that the AMP-driven compaction of nucleic acids and modulation of their phase transitions constitute a previously unrecognised mechanism by which AMPs exert their antibacterial effects. The development of antimicrobials that target nucleic acid phase transitions may become an attractive route to finding effective and long-lasting antibiotics.

Date: 2023
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DOI: 10.1038/s41467-023-42374-4

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