Discovery of dimethyl quaternary ammonium salt based on harmane against MRSA infections by multi-target mechanism

With rising antimicrobial resistance and continuous failure of conventional therapies, innovative drug development against methicillin-resistant Staphylococcus aureus (MRSA) is crucial for effective clinical treatment. Here, new dimethyl quaternary ammonium salt 5b derived from harmane were designed, exhibiting potent anti-MRSA activities including clinical strains (MIC = 0.25-0.5 μg/mL) with rapid bactericidal mode, slow resistance acquisition, favorable stability and low cytotoxicity and hemolytic toxicity. Moreover, compound 5b demonstrated effective therapeutic effects in the mouse skin Infection model, being competitive compared with vancomycin. Mechanistic investigations revealed that compound 5b inhibited biofilm formation by reducing extracellular Polysaccharides, damaged the structure and function of cell wall by binding to peptidoglycan and lipoteichoic acids (LTA), targeted to membranes by interaction with phosphatidylethanolamine (PE) accompanying with depolarization, permeability alteration and integrity damage. Especially, compound 5b could further reduce intracellular metabolic activity, disrupt the redox balance with increasing levels of Reactive Oxygen Species (ROS) and decreasing activity of glutathione (GSH) as well as superoxide dismutase (SOD). Moreover, compound 5b could bind to DNA driven by entropy and enthalpy via a spontaneous process. Overall, this work provided a prominent anti-MRSA lead candidate, managing resistant infections by multi-target mechanism.

Anti-MRSA; Harmane; Multi-target mechanism; Quaternary ammonium.