Abstract
The increasingly limited therapeutic options for the treatment of infections caused by multi-resistant Gram-negative bacteria due to the alarming increase in bacteria resistance, renewed interest in photodynamic inactivation (PDI) of bacteria. We address PDI of multi-resistant bacteria with a new family of cationic tetra-imidazolyl phthalocyanines bearing a diversity of cationizing alkylic chain sizes, degrees of cationization and coordinating metals. The antimicrobial activities of the phthalocyanines under white light against Gram-positive and Gram-negative bacteria have remarkable differences in efficacy. We relate their spectroscopic and photophysical properties with the generation of reactive oxygen species (ROS), biological performance and structural features. We show that sub-micromolar concentrations of a Zn(II) tetra-ethyl cationic phthalocyanine reduce colonies of Gram-negative bacteria (E. coli, P. aeruginosa) and C. albicans by 7 log units while leaving mammalian cells unharmed. This is a new lead to address hard-to-treat localized infections.
Highlights
The increase of bacteria multi-drug resistance is becoming a major social threat and a growing economic burden to healthcare systems [1]
It is accepted that, compared to classical antibiotic therapies, photodynamic inactivation (PDI)-treated bacteria are less prone to development of multidrug resistance (MDR) [15,20e23]
The cationic phthalocyanines used in this study were synthesized according to Scheme 1. 4-(1H-Imidazol-1-yl)phthalonitrile 1 was prepared by reacting commercial 4-nitrophthalonitrile with imidazole in DMF, at room temperature, in the presence of K2CO3, and was isolated in 56% yield
Summary
The increase of bacteria multi-drug resistance is becoming a major social threat and a growing economic burden to healthcare systems [1]. Aroso et al / European Journal of Medicinal Chemistry 184 (2019) 111740 clearly understood [11] The understanding of such factors may guide the design and development of better antimicrobial photosensitizers, capable of inactivating Gram-positive bacteria and the very challenging Gram-negative bacteria. Attempts to increase the potency of phthalocyanines for PDI should consider the following factors: i) adding cationic groups to increase electrostatic interaction with the outer membrane improves PDI of Gram-negative bacteria and increases hydrophilicity [8,49]; ii) increasing of the size of cationizing alkyl chain favours photosensitizer uptake [50] and may result in enhanced antimicrobial activity [55,56]. For the first time, to reduce by 7 logs units the number of colonies of two Gram-negative bacteria (E. coli and P. aeruginosa) using nanomolar photosensitizer concentrations under conditions of negligible phototoxicity towards human cells
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