Novel β-Carboline Derivative ZLWH-67 Exerts Potent Anti-MRSA Activity through Multiple Mechanisms

Infections induced by methicillin-resistant Staphylococcus aureus (MRSA) are serious, highlighting the urgent need for exploring new antibacterial agents. Here, we report a new β-carboline derivative, termed ZLWH-67, that displays potent antibacterial activity against MRSA. ZLWH-67 exhibited bactericidal properties, low cytotoxicity and hemolytic toxicity, and good safety in vivo and was not susceptible to resistance. The potential antibacterial mechanisms of ZLWH-67 were studied by RNA-seq analysis and verified by RT-PCR. The results indicated that ZLWH-67 might exert its effects through multiple mechanisms, including biofilm formation suppression, membrane integrity disruption, energy metabolism disturbance, oxidative stress, and DNA damage. Further mechanistic studies demonstrated that ZLWH-67 potently inhibited biofilm formation and disrupted the integrity of the cell membrane. The disruption resulted in cytoplasmic DNA leakage, increased intracellular ROS, and inhibition of DNA synthesis, ultimately accelerating bacterial death. Notably, ZLWH-67 showed anti-MRSA efficacy in mouse skin and pneumonia infection models, comparable to vancomycin, emphasizing the potential as a promising anti-MRSA candidate.