College of Chemistry and Materials Science, Jiangsu Key Laboratory of Bio-functional Materials, Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials, Key Laboratory of Applied Photochemistry, Nanjing Normal University, Nanjing 210023, China.
College of Chemistry and Materials Science, Jiangsu Key Laboratory of Bio-functional Materials, Jiangsu Collaborative Innovation Centre of Biomedical Functional Materials, Key Laboratory of Applied Photochemistry, Nanjing Normal University, Nanjing 210023, China.
J Inorg Biochem. 2024 Aug;257:112599. doi: 10.1016/j.jinorgbio.2024.112599. Epub 2024 May 11.
The urgent global health problem of antimicrobial resistance (AMR) calls for the discovery of new antibiotics with innovative modes of action while considering the low toxicity to mammalian cells. This paper proposes a novel strategy for designing antibiotics with selective bacterial toxicity by exploiting the positional differences of electron transport chains (ETC) in bacterial and mammalian cells. The focus is on cytochrome c (cyt C) and its maturation system in E. coli. The catalytic oxidative activity of metallophthalocyanine (MPc), which have a distinctive M-N4 structure, is being investigated. Unlike previous applications based on light-activated reactive oxygen species (ROS) generation, this study exploits the ability of MPcs to oxidize Fe to Fe in cyt C and catalyze the formation of disulfide bonds between cysteine residues to interfere with cyt C maturation, disrupt the bacterial respiratory chain and selectively kills bacteria. In contrast, in mammalian cells, these MPcs are located in the lysosomes and cannot access the ETC in the mitochondria, thus achieving selective bacterial toxicity. Two MPcs that showed effective antibacterial activity in a wound infection model were identified. This study provides a valuable reference for the design of novel antibiotics based on M-N4-based metal complex molecules.
抗菌药物耐药性（AMR）是一个紧迫的全球健康问题，需要开发具有创新作用模式的新型抗生素，同时考虑到对哺乳动物细胞的低毒性。本文提出了一种通过利用细菌和哺乳动物细胞中线粒体电子传递链（ETC）位置差异来设计具有选择性细菌毒性的抗生素的新策略。本文的重点是细胞色素 c（cyt C）及其在大肠杆菌中的成熟系统。本文研究了金属酞菁（MPc）的催化氧化活性，其具有独特的 M-N4 结构。与以前基于光激活活性氧（ROS）生成的应用不同，本研究利用 MPc 将 Fe 氧化为 cyt C 中的 Fe，并催化半胱氨酸残基之间形成二硫键，从而干扰 cyt C 成熟、破坏细菌呼吸链并选择性杀死细菌。相比之下，在哺乳动物细胞中，这些 MPc 位于溶酶体中，无法进入线粒体中的 ETC，从而实现了选择性的细菌毒性。确定了两种在伤口感染模型中具有有效抗菌活性的 MPc。本研究为基于 M-N4 金属配合物分子设计新型抗生素提供了有价值的参考。
