Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides.
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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.
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Acknowledgements: The research leading to these results has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant MicroREvolution (agreement no. 101023060; T.S.) and the ERC grant DiProPhys (agreement ID 10100161, T.P.J.K.); the Royall Scholarship (N.A.E.); Global Research Technologies Novo Nordisk A/S (H.A., T.P.J.K.); the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grants PhysProt (agreement no. 337969; T.P.J.K.); the Frances and Augustus Newman Foundation (T.S.); the Schmidt Science Fellowship programme in partnership with the Rhodes Trust (K.L.S.); St. John’s College Junior Research Fellowship (K.L.S.), the Harding Distinguished Postgraduate Scholar Programme (T.J.W.); Boehringer Ingelheim Fonds (K.K.G.); and Wellcome Trust (213437/Z/18/Z, A.B.).
Funder: Frances and Augustus Newman Foundation; doi: https://doi.org/100007898
Funder: The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grants PhysProt (agreement no. 33796) ERC grant DiProPhys (agreement ID 10100161)
Funder: Boehringer Ingelheim Fonds (Stiftung für medizinische Grundlagenforschung); doi: https://doi.org/501100001645
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2041-1723
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European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (101023060)
European Commission Horizon 2020 (H2020) ERC (101001615)