Tuning the Molecular Structure of Corroles to Enhance the Antibacterial Photosensitizing Activity

GONZALEZ LOPEZ, EDWIN J.; MARTINEZ SOL, R.; AIASSA, VIRGINIA; SANTAMARINA, SOFÍA C.; DOMÍNGUEZ, RODRIGO E. ; DURANTINI, EDGARDO N.; HEREDIA, DANIEL A.

pharmaceutics

MDPI - Publisher of Open Access Journals

Año: 2023

1999-4923

The increase in the antibiotic resistance of bacteria is a serious threat to public health.Photodynamic inactivation (PDI) of micro-organisms is a reliable antimicrobial therapy to treat a broadspectrum of complex infections. The development of new photosensitizers with suitable properties isa key factor to consider in the optimization of this therapy. In this sense, four corroles were designedto study how the number of cationic centers can influence the efficacy of antibacterial photodynamictreatments. First, 5,10,15-Tris(pentafluorophenyl)corrole (Co) and 5,15-bis(pentafluorophenyl)-10-(4-(trifluoromethyl)phenyl)corrole (Co-CF3) were synthesized, and then derivatized by nucleophilicaromatic substitution with 2-dimethylaminoethanol and 2-(dimethylamino)ethylamine, obtainingcorroles Co-3NMe2 and Co-CF3-2NMe2, respectively. The straightforward synthetic strategy gaverise to macrocycles with different numbers of tertiary amines that can acquire positive charges inan aqueous medium by protonation at physiological pH. Spectroscopic and photodynamic studiesdemonstrated that their properties as chromophores and photosensitizers were unaffected, regardlessof the substituent groups on the periphery. All tetrapyrrolic macrocycles were able to produce reactiveoxygen species (ROS) by both photodynamic mechanisms. Uptake experiments, the level of ROSproduced in vitro, and PDI treatments mediated by these compounds were assessed against clinicalstrains: methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae. In vitro experimentsindicated that the peripheral substitution significantly affected the uptake of the photosensitizers bymicrobes and, consequently, the photoinactivation performance. Co-3NMe2 was the most effectivein killing both Gram-positive and Gram-negative bacteria (inactivation > 99.99%). This work lays thefoundations for the development of new corrole derivatives having pH-activable cationic groups andwith plausible applications as effective broad-spectrum antimicrobial photosensitizers.