Le Guern Florent, Sol Vincent, Ouk Catherine, Arnoux Philippe, Frochot Céline, Ouk Tan-Sothea
Université de Limoges, Laboratoire de Chimie des Substances Naturelles , EA 1069, 123 Avenue Albert Thomas, 87060 Limoges, CEDEX, France.
Université de Limoges, BISCEm , 87000 Limoges, France.
Bioconjug Chem. 2017 Sep 20;28(9):2493-2506. doi: 10.1021/acs.bioconjchem.7b00516. Epub 2017 Sep 11.
A novel compound consisting of a cationic porphyrin covalently attached to a derivative of polymyxin B has been synthesized and presents enhanced activity and targeting properties compared to the usual cationic porphyrins recognized as efficient photosensitizers in photodynamic antimicrobial chemotherapy (PACT). A synthesis pathway was established to preserve the bactericidal activity of the peptide. Accordingly, the N-terminal amino acid (l-2,4-diaminobutyric acid) of polymyxin B (PMB) was switched for a cysteine residue. Then, the resulting derivative of PMB was covalently bound to 5-(4-aminophenyl)-10,15,20-tri(4-N-methylpyridyl)-21H,23H-porphyrin using a thiol-maleimide "click" coupling. The peptide-coupled photosensitizer has demonstrated an improved PACT efficiency compared to the cationic porphyrin alone. This enhancement has been observed against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in particular. Flow cytometry analyses and confocal imaging microscopy demonstrated that the porphyrin-peptide conjugate selectively adhered to the cell walls of either Gram-positive or Gram-negative bacteria, thus justifying the damages induced by singlet oxygen production.
一种由共价连接到多粘菌素B衍生物上的阳离子卟啉组成的新型化合物已被合成，与在光动力抗菌化疗（PACT）中被认为是高效光敏剂的普通阳离子卟啉相比，它具有增强的活性和靶向特性。建立了一条合成途径以保留该肽的杀菌活性。因此，将多粘菌素B（PMB）的N端氨基酸（L-2,4-二氨基丁酸）替换为半胱氨酸残基。然后，使用硫醇-马来酰亚胺“点击”偶联将所得的PMB衍生物与5-(4-氨基苯基)-10,15,20-三(4-N-甲基吡啶基)-21H,23H-卟啉共价结合。与单独的阳离子卟啉相比，肽偶联的光敏剂已显示出提高的PACT效率。特别是在针对金黄色葡萄球菌、铜绿假单胞菌和大肠杆菌时观察到了这种增强。流式细胞术分析和共聚焦成像显微镜表明，卟啉-肽缀合物选择性地粘附在革兰氏阳性或革兰氏阴性细菌的细胞壁上，从而证明了单线态氧产生所引起的损伤。
