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

The escalation of multidrug-resistant bacterial infections, especially infections caused by methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent need for novel antimicrobial drugs. Here, we synthesized a series of amphiphilic 2-phenyl-1H-phenanthro­[9,10-d]­imidazole-antimicrobial peptide (AMP) mimic conjugates (III1–30). Among them, compound III13 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, III13 demonstrated rapid bactericidal efficacy and was less susceptible to causing bacterial resistance. Mechanistic studies revealed that III13 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, III13 possessed good fluorescence properties with potential for further dynamic monitoring of the antimicrobial process. Notably, III13 showed better in vivo efficacy against MRSA compared to vancomycin, suggesting its potential as a promising candidate for anti-MRSA medication.

多重耐药菌感染态势日益严峻，尤其是耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）引发的感染，凸显了开发新型抗菌药物的迫切需求。本研究合成了一系列两亲性2-苯基-1H-菲并[9,10-d]咪唑-抗菌肽（antimicrobial peptide, AMP）模拟物缀合物（III₁₋₃₀）。其中化合物III₁₃对革兰氏阳性菌及临床分离MRSA菌株展现出优异的抗菌活性，最低抑菌浓度（minimum inhibitory concentration, MIC）为0.5~2 μg/mL，同时具备高膜选择性与低细胞毒性。此外，相较于传统临床抗生素，III₁₃展现出快速杀菌效能，且不易诱导细菌产生耐药性。机制研究表明，III₁₃通过靶向细菌膜上的磷脂酰甘油（phosphatidylglycerol, PG）破坏膜完整性，进而引发胞内活性氧（reactive oxygen species, ROS）水平升高、蛋白质与DNA渗漏，最终导致细菌死亡。此外，III₁₃具备良好的荧光特性，有望用于抗菌过程的动态监测。值得注意的是，相较于万古霉素，III₁₃在体内展现出更优的抗MRSA药效，表明其具备开发为抗MRSA候选药物的潜力。