Modulating Nucleic Acid Phase Transitions as a Mechanism of Action for Cell-Penetrating Antimicrobial Peptides

Abstract

Antimicrobial peptides (AMPs) are a vital part of the immune system that helps combat bacterial infections by disrupting the bacterial cell membrane or interacting with intracellular targets. However, the mechanisms by which AMPs act on intracellular targets are not well understood. Using machine learning-based sequence analysis, we have discovered that a significant number of AMPs have a strong tendency to form liquid-like condensates in the presence of nucleic acids, a process known as phase separation. We have demonstrated 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. We propose 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. These findings open up exciting possibilities for the development of antimicrobials that target nucleic acid phase transitions.

Host defense amyloids: Biosensors of the immune system?

“…Indeed, there is a striking similarity in the structural, biophysical, and functional properties of AMPs and amyloids 1 . Both can undergo phase transitions progressing from a liquid‐liquid separation to more advanced assembly states of gel and solid including protofibrils and fibrils with characteristic cross α‐helical and cross‐β sheet properties 2–4 (Figure 1). These structures can create pores in membranes resulting in antimicrobial activity and cytotoxicity.…”