Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free...

Area of Science:

• Microbiology
• Drug Discovery
• Biochemistry

Background:

• Bacterial resistance necessitates innovative multitargeting strategies.
• Existing methods face pharmacokinetic, pharmacodynamic, and cytotoxicity challenges.

Purpose of the Study:

• To propose a bacterial-specific global disruption approach for expanded multitargeting.
• To investigate ligand-receptor interaction-induced intracellular aggregation as a novel antibacterial mechanism.

Main Methods:

• Designed a diarginine peptidomimetic for DNA-induced intracellular aggregation.
• Analyzed macromolecule binding, cytoplasmic localization, and bacterial stress responses.
• Evaluated in vivo antimicrobial efficacy in murine infection models.

Main Results:

• Intracellular aggregates interfered with essential bacterial functions and caused "inside-out" membrane rupture.
• Demonstrated robust antibacterial activity and suppression of drug resistance.
• Showcased favorable biocompatibility and pharmacokinetic properties, with in vivo efficacy.

Conclusions:

• Ligand-receptor interaction-induced intracellular aggregation offers a unique, globally disruptive multitargeting effect.
• This approach is fundamentally different from classic DNA or membrane binding mechanisms.
• Potential applications include treating bacterial pathogens, tumor cells, and infected tissues.