Mi Le, Xu Tao, Peng Ying-Yuan, Strakhovskaya Marina G, Zhang Yi-Jing, Meerovich Gennady A, Nyokong Tebello, Yan Yi-Jia, Chen Zhi-Long
Department of Pharmaceutical Science and Technology, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China.
Huadong Hospital, Fudan University, Shanghai, 200040, China.
Eur J Med Chem. 2025 Jun 5;290:117558. doi: 10.1016/j.ejmech.2025.117558. Epub 2025 Mar 22.
Antimicrobial photodynamic therapy (aPDT) has emerged as a promising strategy for addressing bacterial infections, particularly those involving biofilm formation. The electrostatic attraction between the negatively charged bacterial cell walls and the cationic charges of photosensitizers facilitates the accumulation of PSs on bacterial surfaces, thereby enhancing aPDT efficacy. In this study, three series of tetracationic tetraaryltetranaphtho[2,3]porphyrins (TNPs), each incorporating different cationic groups with alkyl chains of varying lengths, were designed and synthesized. Their photodynamic inactivation efficacy against S. aureus, E. coli and C. albicans was evaluated, respectively. These TNPs exhibited strong absorption at ∼730 nm with high molar extinction coefficients (>51,500 L·mol·cm), fluorescence emission at ∼758 nm and efficient singlet oxygen generation capabilities. Among them, TNPs with shorter alkyl chains (I, II and Ⅲ) exhibited enhanced phototoxicity against planktonic microbes, with I (containing pyridinium substituents) showing the highest activity. These three compounds effectively disrupted mature S. aureus biofilms, with Ⅲ (bearing diethylmethylammonium groups) demonstrating superior biofilm eradication capabilities. These findings highlight the dual antibacterial and biofilm-disrupting potential of these ArTNP derivatives. Furthermore, their selective toxicity toward bacterial cells over mammalian cells at therapeutic doses provides a foundation for developing safer antimicrobial agents, offering promising alternatives to antibiotics for tackling drug-resistant pathogens and persistent biofilm-associated infections.
抗菌光动力疗法（aPDT）已成为一种有前景的治疗细菌感染的策略，尤其是那些涉及生物膜形成的感染。带负电荷的细菌细胞壁与光敏剂的阳离子电荷之间的静电吸引促进了光敏剂在细菌表面的积累，从而提高了aPDT的疗效。在本研究中，设计并合成了三个系列的四阳离子四芳基四萘并[2,3]卟啉（TNPs），每个系列都含有不同的阳离子基团和不同长度的烷基链。分别评估了它们对金黄色葡萄球菌、大肠杆菌和白色念珠菌的光动力灭活效果。这些TNPs在730 nm处表现出强烈吸收，具有高摩尔消光系数（>51,500 L·mol·cm），在758 nm处有荧光发射，并且具有高效的单线态氧生成能力。其中，具有较短烷基链的TNPs（I、II和III）对浮游微生物表现出增强的光毒性，I（含有吡啶鎓取代基）表现出最高活性。这三种化合物有效地破坏了成熟的金黄色葡萄球菌生物膜，III（带有二乙甲基铵基团）表现出卓越的生物膜根除能力。这些发现突出了这些芳基TNP衍生物的双重抗菌和生物膜破坏潜力。此外，它们在治疗剂量下对细菌细胞相对于哺乳动物细胞的选择性毒性为开发更安全的抗菌剂奠定了基础，为应对耐药病原体和持续性生物膜相关感染提供了有前景的抗生素替代品。
