Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide

摘要

The emergence of multidrug-resistant bacteria creates an urgent need for alternative antibiotics with new mechanisms of action. In this study, we synthesized a novel type of antimicrobial agent, Ac r_3-NLS, by conjugating hydrophobic acridines to the N-terminus of a nuclear localization sequence(NLS), a short cationic peptide. To further improve the antimicrobial activity of our agent, dimeric(Acr_3-NLS)_2 was simultaneously synthesized by joining two monomeric Acr_3-NLS together via a disulfide linker. Our results show that Acr_3-NLS and especially(Acr_3-NLS)_2 display signifi cant antimicrobial activity against gramnegative and gram-positive bacteria compared to that of the NLS. Subsequently, the results derived from the study on the mechanism of action demonstrate that Acr_3-NLS and(Acr_3-NLS)_2 can kill bacteria by membrane disruption and DNA binding. The double targets—cell membrane and intracellular DNA—will reduce the risk of bacteria developing resistance to Acr_3-NLS and(Acr_3-NLS)_2. Overall, this study provides a novel strategy to design highly eff ective antimicrobial agents with a dual mode of action for infection treatment.