Enhanced Photobactericidal and Targeting Properties of a Cationic Porphyrin following the Attachment of Polymyxin B

• DOI: 10.1021/acs.bioconjchem.7b00516
• Publication Date: 2017-08-30T19:29:46Z
• Authors: Florent Le Guern; Vincent Sol; Catherine Ouk; Philippe Arnoux; Céline Frochot; Tan-Sothea Ouk
• Keywords: 0301 basic medicine; Staphylococcus aureus; Porphyrins; antimicrobial peptide; [CHIM.THER] Chemical Sciences/Medicinal Chemistry; cationic porphyrin; [CHIM.THER]Chemical Sciences/Medicinal Chemistry; Cell Line; 03 medical and health sciences; Cations; thiol-click; Escherichia coli; Humans; PACT; targeting; Polymyxin B; Photosensitizing Agents; Bacteria; [CHIM.ORGA]Chemical Sciences/Organic chemistry; polymyxin B; Bacterial Infections; [CHIM.ORGA] Chemical Sciences/Organic chemistry; Anti-Bacterial Agents; 3. Good health; Pseudomonas aeruginosa

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.