Overcoming Methicillin-Resistant Staphylococcus aureus Infections by Disrupting Membrane Integrity and Inducing DNA Degradation with A Dual-Mechanism Fluorescent Phenanthro[9,10-d]imidazole Molecule

The rise of multidrug-resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), poses a serious threat to human health, necessitating an urgent need to develop innovative antibacterials with multifunctions for this. Here, focusing on integrating multi-antimicrobial mechanisms with visual monitoring, we report a novel phenanthro[9,10-d]imidazole fluorogen 9b, outstanding for its antibacterial effects against S. aureus and various clinical MRSA isolates (minimum inhibitory concentration = 0.5 to 1 μg/ml) with rapid bactericidal activity, high membrane selectivity, and low susceptibility to drug resistance. Further investigation revealed its dual antimicrobial mechanisms of action by concurrently disrupting bacterial cell membranes and inducing bacterial DNA degradation to accelerate bacterial death. Ultraviolet–visible and fluorescence spectroscopy studies showed that the fluorescence intensity of 9b was dramatically enhanced when it interacted with S. aureus. Notably, in vivo studies demonstrated that 9b effectively treated both skin and thigh MRSA infections, showing a favorable safety profile and superior efficacy compared to the first-line antibiotic vancomycin. The “dual-mechanism” fluorescent phenanthro[9,10-d]imidazole fluorogen 9b holds promise as a candidate for developing innovative antibacterial agents that enable simultaneous real-time diagnosis and treatment.