Synthesis and anti-MRSA activity of quaternized small molecule antimicrobial peptide mimics based on norharmane

The escalating prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections, coupled with the diminishing efficacy of existing antimicrobial agents, has created an urgent need for novel Antibacterial therapeutics. Here, three classes of quaternized small molecule antimicrobial peptide mimics (SMAPMs) incorporating norharmane skeleton were prepared based on molecular splicing strategy. Among them, compound 10c demonstrated excellent activity against MRSA, exhibiting a low minimum inhibitory concentration (MIC) of 0.25 μg/mL in vitro, coupled with significant therapeutic efficacy in a murine skin Infection model in vivo. Additionally, compound 10c possessed rapid bactericidal property, low tendency to induce resistance, good plasma stability, and acceptable biosafety in vitro and in vivo. Mechanistic studies revealed that 10c exerts its multi-target Antibacterial effects through several distinct pathways: (1) inhibition of biofilm formation; (2) cell wall disruption via interactions with peptidoglycan and lipoteichoic acids; (3) membrane targeting characterized by depolarization, altered permeability, and structural integrity loss; (4) reduction of metabolic activity; (5) disruption of cellular redox homeostasis; and (6) DNA binding. These findings demonstrate that compound 10c has the potential to be a candidate drug, while simultaneously providing a theoretical foundation for future anti-MRSA drug development through the SMAPMs strategy.

Antibacterial activity; Multi-target mechanism; Norharmane; SMAPMs.