The PORP2PS project has as the main goal to develop new derivatives based on the conjugation of easily accessible porphyrin scaffolds with triphenylphosphonium salts and to exploit their efficacy as non-immobilized and immobilized photosensitizers (PS) in the photodynamic inactivation (PDI) of pathogenic microorganisms (MO), namely the multidrug-resistant (MDR) ones.
Currently, one of the greatest public health challenges is associated to antibiotic resistance, due to the inadequate prescription and overuse of antibiotics, with the consequent growing number of infections caused by MDR bacteria and viruses. Combating these threats is a public health priority that requires a collaborative global approach across sectors. The methodology behind PDI is being pointed out by the scientific and medical community as a promising and efficient alternative to the use of antibiotics.
Porphyrin derivatives adequately functionalized can act as broad-spectrum antimicrobial agents, after being properly activated by visible light in the presence of bimolecular oxygen, targeting pathogens such as MDR viruses, fungi and bacteria. It is well-established that Gram-(-) bacteria are less susceptible to PDI than Gram-(+) bacteria due to their more complex cellular wall, but this limitation can be overcome by using PS positively charged (alternatively to neutral and anionic PS) able to destabilize the cell wall organization through electrostatic interactions, and consequently facilitating the PS actuation. Most of these PS can be obtained through the post-functionalization of natural porphyrin derivatives recurring to hard and complex synthetic routes, or the use of 5,10,15,20-tetrakis(N-methyl-4-pyridinium)porphyrin (TMPPy) and analogous, limiting the synthetic approaches available to improve the PS efficiency. Usually, it is restricted to the use of alkylating agents for the insertion of positive charges in neutral porphyrins bearing pyridyl or amine functionalities.
Phosphonium salts have been widely studied as antitumoral but also as broad-spectrum antimicrobial drugs due to their relatively lipophilic character.
PORP2PS proposes new solutions for the structures of porphyrin derivatives that are expected to allow significant advances in the development of new photo-antimicrobial compounds/materials to be used in photodynamic inactivation of MO and to bring a high impact in this emerging area. The PORP2PS project aims to couple porphyrin macrocycles with triphenylphosphonium (TPP+) moieties to explore the symbiotic effect of both units towards pathogenic MO. Simple methodologies involving alkylation, nucleophilic substitution, amidation, esterification or click chemistry reactions will be exploited in the conjugation of both bioactive partners. The porphyrin moiety will be able to generate reactive oxygen species (ROS) while the terminal phosphonium unit will act as a disruptor of the bacterial membrane by interaction with the lipid membrane, thus expecting a high antimicrobial effect. Additionally, since the positive charge will be introduced by the TPP+ moiety, the proposal enables the use of other functional groups in addition to pyridyl rings, significantly increasing the synthetic versatility and the library of photo-antimicrobials suitable for the target application.
The use of polyether and polyamine chains as spacers connecting the porphyrin and TPP+ units may lead to conjugates with better solubility in aqueous media reducing the possibility of aggregation. Moreover, if needed, the cationization of polyamine chains will allow, to increase the number of positive charges and consequently to improve the PS actuation.
It is expected that the new porphyrin-TPP+ based PSs produces high amounts of ROS, namely singlet oxygen, and that the combination of this inherent property of the porphyrin derivatives with the antimicrobial properties of the TPP+ units will lead to a symbiotic effect conducting to highly effective photo-antimicrobial molecules able to photoinactivate efficiently either Gram-(+) and Gram-(-) multidrug-resistant bacteria.
The immobilization of the new PSs is an essential requirement to make their application more practical and environmentally feasible. Thus, the new PSs with the most promising features to act as photo-antimicrobial agents will be immobilized covalently or non-covalently in solid matrices. Its anchorage in magnetic nanoparticles (NPs) and/or their use as doping agents in low-cost, environmentally-friendly, and reusable polysaccharide-based films or hydrogels (starch, cellulose and chitosan), will allow the preparation of new photoactive materials based on accessible, low-cost and ecological raw materials. Is expected that the use of supported PSs allows a fast and efficient photoinactivation.
It is anticipated that the quality, expertise, know-how and interdisciplinarity of the team involved in the PORP2PS project will allow obtaining promising compounds/materials with antimicrobial properties.