Cationic, amphipathic small molecules based on a triazine-piperazine-triazine scaffold as a new class of...

Poor proteolytic resistance, toxicity and salt/serum sensitivity of antimicrobial peptides (AMPs) limits their practical clinical application. Here, to overcome these drawbacks of AMPs and develop novel antimicrobial agents, a series of small molecules based on a triazine-piperazine-triazine scaffold that mimic the cationic amphipathic structure of AMPs were synthesized and evaluated their potential as a new class of antimicrobial agents. All designed compounds showed strong antimicrobial activity and negligible hemolytic activity. Particularly, five compounds (9, 11, 12, 15, and 16) presented excellent cell selectivity with proteolytic resistance, salt/serum stability and anti-inflammatory activity against lipopolysaccharide (LPS)-induced inflammation. These five compounds exhibited similar or 2-4 fold higher antimicrobial activity than melittin against six antibiotic-resistant bacteria tested. Similar to the intracellular-targeting AMP, buforin-2, these compounds displayed an intracellular mode of antimicrobial action. These compounds showed potent biofilm inhibitory and eradicating activities against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Additionally, these compounds displayed synergistic or additive effects when combined with selected clinically used antibiotics. Furthermore, these compounds have been proven to inhibit pro-inflammatory cytokine release by directly binding to LPS and blocking the interaction between LPS and CD14/TLR4 receptor in LPS-stimulated RAW264.7 macrophage cells. Overall, our results demonstrate the potential of the designed compounds as a novel class of multifunctional antimicrobial agents to combat bacterial infection.