Song Yun, Wang Jing, Sun Yajun, Dong Shijia, Yu Guangying, Lin Wenjing, Xiong Yinhua, Tan Yanhui, Xiong Yanshi, Jiang Guijuan, Wang Jintao, Liao Xiangwen, Liu Lianghong
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science&Technology Normal University, Nanchang 330013, China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China.
J Inorg Biochem. 2025 Feb;263:112772. doi: 10.1016/j.jinorgbio.2024.112772. Epub 2024 Nov 6.
The rise of antibiotic resistance has posed a great threat to human's life, thus develop novel antibacterial agents is urgently needed. It worthies to noted that Ru-based antibacterial agents often showed robust potency against Gram-positive pathogens, disrupted bacterial membrane and avoided bacterial resistance, making they promising antibiotic candidates. However, they are generally less active when applied to negative pathogens. To address this problem, a Ru-based metalloantibiotic (RuN) modified with a nitrothiophene moiety, which can target bacterial efflux pump, was designed and evaluated in this work. A series of assays demonstrated that RuN not only fully retained the advantages of Ru-based agents, such as destroyed bacterial membrane and induced reactive oxygen species production, but also can targeted bacterial efflux pumps. Of course, these properties make it effective in killing both Gram-positive and negative pathogens, its MIC values against Staphylococcus aureus and Escherichia coli lies at 3.125 and 6.25 μg/mL, respectively. Importantly, RuN also showed low toxicity and has robust anti-infective potency in two animal infection models. Together, our results paved an alternative way to enhance the anti-infective efficacy of Ru-based agents against resistant negative bacteria.
抗生素耐药性的上升对人类生命构成了巨大威胁，因此迫切需要开发新型抗菌剂。值得注意的是，钌基抗菌剂通常对革兰氏阳性病原体表现出强大的效力，能够破坏细菌膜并避免细菌耐药，使其成为有前景的抗生素候选物。然而，当应用于阴性病原体时，它们通常活性较低。为了解决这个问题，在本研究中设计并评估了一种用硝基噻吩部分修饰的钌基金属抗生素（RuN），其可以靶向细菌外排泵。一系列实验表明，RuN不仅完全保留了钌基制剂的优点，如破坏细菌膜和诱导活性氧生成，而且还能靶向细菌外排泵。当然，这些特性使其在杀死革兰氏阳性和阴性病原体方面都有效，其对金黄色葡萄球菌和大肠杆菌的最低抑菌浓度值分别为3.125和6.25μg/mL。重要的是，RuN在两种动物感染模型中也显示出低毒性和强大的抗感染效力。总之，我们的结果为提高钌基制剂对抗耐药阴性细菌的抗感染疗效开辟了一条替代途径。
