One-pot synthesis of a cyclic antimicrobial peptide-conjugated phthalocyanine for synergistic chemo-photodynamic killing of multidrug-resistant bacteria

Abstract

Multidrug-resistant (MDR) bacteria pose a serious threat to public health globally. Among the various antimicrobial modalities that have recently emerged, photodynamic therapy has received considerable attention because of its various potential advantages, including the unlikelihood of inducing drug resistance. A facile synthetic approach is reported to prepare a phthalocyanine-based photosensitizer conjugated with a cyclic bactenecin peptide. This one-pot procedure that involves site-selective alkylation of the two cysteine residues of a linear bactenecin peptide followed by Diels–Alder reaction leads to the formation of the conjugate labeled as cBac-Pc in 27% isolated yield. As shown by confocal fluorescence microscopy, this conjugate shows selective affinity toward bacterial over mammalian cells. It can also induce synergistic cytotoxic effects due to the cyclic peptide and phthalocyanine against a spectrum of Gram-positive and Gram-negative bacterial strains, including two ATCC-type strains and two clinical isolates of MDR bacterial strains. It is believed that the inhibition mechanism is based on the physical destruction of the cell membrane due to the cyclic peptide followed by photodynamic action induced by the phthalocyanine unit.