Development of Membrane-Targeting Fluorescent 2-Phenyl-1<i>H</i>-phenanthro[9,10-<i>d</i>]imidazole-Antimicrobial Peptide Mimic Conjugates against Methicillin-Resistant <i>Staphylococcus aureus</i>

Abstract

The escalation of multidrug-resistant bacterial infections, especially infections caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), underscores the urgent need for novel antimicrobial drugs. Here, we synthesized a series of amphiphilic 2-phenyl-1<i>H</i>-phenanthro[9,10-<i>d</i>]imidazole-antimicrobial peptide (AMP) mimic conjugates (<b>III1</b>-<b>30</b>). Among them, compound <b>III13</b> exhibited excellent antibacterial activity against G+ bacteria and clinical MRSA isolates (MIC = 0.5-2 μg/mL), high membrane selectivity, and low toxicity. Additionally, compared with traditional clinical antibiotics, <b>III13</b> demonstrated rapid bactericidal efficacy and was less susceptible to causing bacterial resistance. Mechanistic studies revealed that <b>III13</b> targets phosphatidylglycerol (PG) on bacterial membranes to disrupt membrane integrity, leading to an increase in intracellular ROS and leakage of proteins and DNA, ultimately causing bacterial cell death. Furthermore, <b>III13</b> possessed good fluorescence properties with potential for further dynamic monitoring of the antimicrobial process. Notably, <b>III13</b> showed better <i>in vivo</i> efficacy against MRSA compared to vancomycin, suggesting its potential as a promising candidate for anti-MRSA medication.