**2. Photosensitizers**

PS are non-toxic molecules capable of absorbing a specific wavelength's energy and transferring it to oxygen molecules present in biological solutions to produce the activated forms of O2 •− and 1 O2. Both forms can produce ROS, which has the ability to promote bacterial cell death through the oxidation of closer organic macromolecules such as membrane components, proteins, lipids, and nucleic acids. In Gram positive bacteria, Pactivated PSs may produce ROS that acts unspecifically on macromolecules present in the envelope, such as lipids and proteins of the plasma membrane, peptidoglycan, and the array of proteins and polysaccharides macromolecules of the matrix (**Figure 1**). A PS has the property of being inert during administration and can be activated by being subjected to a specific wavelength.

#### **2.1 Most used photosensitizer for PDT over** *Staphylococcus aureus*

**Table 1** summarized some of the more recent efforts to eradicate *S. aureus* by PDT. Porphyrins are an important class of natural macrocyclic molecules found in biological compounds and play an essential role in the metabolism of living organisms. The best known natural porphyrins are the heme group and chlorophyll. The heme group is a porphyrin-iron complex that is part of many active sites of different proteins, such as hemoglobin, myoglobins, and cytochromes. Uroporphyrin and coproporphyrin are the oxidation products of their respective porphyrinogens, which are the proper substrates in the biosynthetic pathway. The basic structure of porphyrin is formed by four pyrrole units interconnected by their alpha carbons linked by methyl bridges. The most commonly used photosensitizer drug in the last decade is porphyrin derivatives, such as the synthetic protoporphyrin Diarginate, T4 Porphyrin, Protoporphyrin IX, Coproporphyrin III, Porphyrin Formulation, among others. However, there are a few studies that have tried to verify whether these natural or synthetic molecules have a photo-oxidative activity with bactericidal action. The vast majority of these studies used porphyrin derivatives under irradiation with the red light of a wavelength range of 618–780 nm. PDT mediated by porphyrin derivatives increased antimicrobial efficacy and significantly reduced bacterial viability [10, 11, 14, 15, 40].

One of the initial studies on this PS was the series by Grinholc *et al*. [13, 16], who evaluated the bactericidal efficacy of PDT mediated by protoporphyrin diarginate over MRSA and MSSA strains in a large number of clinical isolates*.* They observed a reduction of 0–3 log10 of MRSA strains and 0.2 to 3 log10 for MSSA strains. Although this study's results were not significant, they paved the way for studying and developing PSs [13]. The 5-aminolevulinic acid (5-ALA), a prodrug that becomes protoporphyrin IX (PP IX) in the target cells, was used as a photosensitizer. Compared to other PSs, 5-ALA is only a natural intermediate in the heme biosynthetic pathway and can be removed rapidly from target cells. More importantly, it is small enough to penetrate the matrix and accumulate in target cells with less toxicity. The antimicrobial activity of 5-ALA-PDT was demonstrated on MRSA's planktonic strain in vitro by Huang *et al*. [37]. Their results showed that the number of living cells decreased as the concentration of the compound augmented. In control groups with solely 5-ALA or light, most of the bacterial cells were alive. Consequently, the photodynamic activity of 5-ALA is dose-dependent [37].




#### *Photodynamic Therapy - From Basic Science to Clinical Research*


**Table 1.**

*List for research and development of* S. aureus *PDT.*
