Synthesis of β-Carboline-Based Dimers and Hybrids and Anti-Methicillin-Resistant Staphylococcus aureus Properties by...

The upsurging antibiotic resistance crisis underscores the urgent need for discovering agents with new molecular scaffolds. Dimerization and hybridization represent the most commonly employed approaches and are promising strategies for developing new antibacterial entities to combat antibiotic resistance. In this study, two series of dimeric β-carbolines and tacrine-β-carboline hybrids were synthesized. The tacrine-β-carboline derivatives demonstrated potent activity against Gram-positive bacteria (MIC = 0.195-50 μg/mL), exhibiting particularly strong inhibition against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic evidence demonstrates that tacrine-β-carboline hybrids exert antibacterial effects by disrupting both bacterial cell wall and membrane integrity and the function of filamentous temperature-sensitive mutant Z (FtsZ), a pivotal cell division protein. Specifically, these compounds drive FtsZ polymerization by promoting monomer assembly and stabilizing the resultant polymeric structures, concomitantly suppressing GTPase activity. Molecular docking and dynamics simulations further elucidated binding interactions within the FtsZ nucleotide-binding domain (NBD). This work might provide an insight into developing novel therapeutics targeting drug-resistant bacterial pathogens.