Synthesis, Characterization, and Photoinduced Antibacterial Activity of Porphyrin-Type Photosensitizers Conjugated to the Antimicrobial Peptide Apidaecin 1b

Abstract

Antimicrobial photodynamic therapy (aPDT) is an emerging treatment for bacterial infections that is becoming increasingly more attractive because of its effectiveness against multi-antibiotic-resistant strains and unlikelihood of inducing bacterial resistance. Among the strategies to enhance the efficacy of PDT against Gram-negative bacteria, the binding to a cationic antimicrobial peptide offers the attractive prospect for improving both the water solubilty and the localization of the photoactive drug in bacteria. In this work we have compared a number of free and apidaecin-conjugated photosensitizers (PSs) differing in structure and charge. Our results indicate that the conjugation of per se ineffective highly hydrophobic PSs to a cationic peptide produces a photosensitizing agent effective against Gram-negative bacteria. Apidaecin cannot improve the phototoxic activity of cationic PSs, which mainly depends on a very high yield of singlet oxygen production in the surroundings of the bacterial outer membrane. Apidaecin-PS conjugates appear most promising for treatment protocols requiring repeated washing after sensitizer delivery.

Oligo- and polypeptide conjugates of cationic porphyrins: binding, cellular uptake, and cellular localization

“…Among others, peptide conjugates were also synthesized either to increase the cellular uptake of porphyrin derivatives or to deliver the peptide moiety to the nucleic acids (Orosz and Csik 2016;Sibrian-Vazquez et al 2010, 2018Dosselli et al 2013). …”

How Does Membrane Oxidation Affect Cell Delivery and Cell Killing?

“…Oxidized lipids and proteins consequently do not behave in the lipid bilayer as their non-oxidized precursors do, and they often contribute to increasing the membrane’s permeability. Electroporation [1], gas plasma [4], and photodynamic techniques [5–7] have already been shown to take advantage of membrane oxidation to achieve cell penetration or cell killing.…”

Antibacterial photodynamic therapy: overview of a promising approach to fight antibiotic-resistant bacterial infections

“…Anionic and neutral porphyrins are generally not recommended for targeting Gram-negative bacteria due to their poor binding efficacy. However, the association of anionic and neutral porphyrins with Gram-negative bacteria can be considerably improved by the conjugation of cationic antimicrobial peptides (CAMPs) or cell penetrating peptides (CPPs) such as apidaecin [42,43], Tat [44], buforin, or magainin [45] to the PS. These PS-peptide conjugates effectively photosensitized E. coli and induced considerable cell death following APDT compared to unconjugated PS.…”