Impact of Conjugation of the Reactive Oxygen Species (ROS)-Generating Catalytic Moiety with Membrane-Active Antimicrobial Peptoids: Promoting Multitarget Mechanism and Enhancing Selectivity

Antimicrobial peptides (AMPs) represent promising therapeutic
modalities
against multidrug-resistant bacterial infections. As a mimic of natural
AMPs, peptidomimetic oligomers like peptoids (i.e., oligo-N-substituted glycines) have been utilized for antimicrobials
with resistance against proteolytic degradation. Here, we explore
the conjugation of catalytic metal-binding motifsthe amino
terminal Cu(II) and Ni(II) binding (ATCUN) motifwith cationic
amphipathic antimicrobial peptoids to enhance their efficacy. Upon
complexation with Cu(II) or Ni(II), the conjugates catalyzed hydroxyl
radical generation, and 22 and 22-Cu exhibited
over 10-fold improved selectivity compared to the parent peptoid,
likely due to reduced hydrophobicity. Cu-ATCUN-peptoids caused bacterial
membrane disruption, aggregation of intracellular biomolecules, DNA
oxidation, and lipid peroxidation, promoting multiple killing mechanisms.
In a mouse sepsis model, 22 demonstrated antimicrobial
and anti-inflammatory efficacy with low toxicity. This study suggests
a strategy to improve the potency of membrane-acting antimicrobial
peptoids by incorporating ROS-generating motifs, thereby adding oxidative
damage as a killing mechanism.