Stable Synthetic Cationic Bacteriochlorins as Selective Antimicrobial Photosensitizers

Abstract

Photodynamic inactivation is a rapidly developing antimicrobial treatment that employs a nontoxic photoactivatable dye or photosensitizer in combination with harmless visible light to generate reactive oxygen species that are toxic to cells. Tetrapyrroles (e.g., porphyrins, chlorins, bacteriochlorins) are a class of photosensitizers that exhibit promising characteristics to serve as broad-spectrum antimicrobials. In order to bind to and efficiently penetrate into all classes of microbial cells, tetrapyrroles should have structures that contain (i) one or more cationic charge(s) or (ii) a basic group. In this report, we investigate the use of new stable synthetic bacteriochlorins that have a strong absorption band in the range 720 to 740 nm, which is in the near-infrared spectral region. Four bacteriochlorins with 2, 4, or 6 quaternized ammonium groups or 2 basic amine groups were compared for light-mediated killing against a Gram-positive bacterium (Staphylococcus aureus), a Gramnegative bacterium (Escherichia coli), and a dimorphic fungal yeast (Candida albicans). Selectivity was assessed by determining phototoxicity against human HeLa cancer cells under the same conditions. All four compounds were highly active (6 logs of killing at 1 M or less) against S. aureus and showed selectivity for bacteria over human cells. Increasing the cationic charge increased activity against E. coli. Only the compound with basic groups was highly active against C. albicans. Supporting photochemical and theoretical characterization studies indicate that (i) the four bacteriochlorins have comparable photophysical features in homogeneous solution and (ii) the anticipated redox characteristics do not correlate with cell-killing ability. These results support the interpretation that the disparate biological activities observed stem from cellular binding and localization effects rather than intrinsic electronic properties. These findings further establish cationic bacteriochlorins as extremely active and selective near-infrared activated antimicrobial photosensitizers, and the results provide fundamental information on structure-activity relationships for antimicrobial photosensitizers.

Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

“…It is known that Gram-negative bacteria are more resistant to photodynamic therapy than Gram-positive species (18). Previous studies by Hamblin's group have shown that even a 10-timeshigher concentration of an antimicrobial is needed to inactivate Gram-negative than Gram-positive microorganisms (19,20).…”

Asthma phenotypes and IgE responses

“…The combination of high-dose allergen exposure along with specific bacteria during the first year of life has been shown to induce a protective effect against atopy and wheezing [79]. The genetic susceptibility to allergen-induced Th2 responses [80,81] may also be explained partly by polymorphisms in the genes encoding IL-4, IL-4R, IL-13, TSLP and/or IL-33 [82][83][84][85]. Polymorphisms in the gene encoding ADAM (a disintegrin and metalloproteinase) 33 actually represent the most robust association not only with asthma and bronchial hyperreactivity, but also with immune-related traits of asthma such as the levels of total IgE and blood eosinophils [86,87].…”

Modifications of Porphyrins and Hydroporphyrins for their Solubilization in Aqueous Media

“…Subsequent N-alkylation of the amines was achieved using standard conditions, and the water-soluble cationic products that precipitated from the CHCl3 reaction mixtures were isolated by precipitation and centrifugation. Some of these compounds were investigated for their efficacy as antimicrobial photosensitizers [64].…”