title: 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 gram-negative 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 microM 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.
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114-2696, USA.
authors.forename: Liyi
authors.initials: L
authors.lastname: Huang
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Huang
authors.forename: Pawel
authors.initials: P
authors.lastname: Mroz
authors.forename: George P
authors.initials: GP
authors.lastname: Tegos
authors.forename: Timur
authors.initials: T
authors.lastname: Zhiyentayev
authors.forename: Sulbha K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Zongshun
authors.initials: Z
authors.lastname: Lu
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Balasubramanian
authors.forename: Michael
authors.initials: M
authors.lastname: Krayer
authors.forename: Christian
authors.initials: C
authors.lastname: Ruzié
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Yang
authors.forename: Hooi Ling
authors.initials: HL
authors.lastname: Kee
authors.forename: Christine
authors.initials: C
authors.lastname: Kirmaier
authors.forename: James R
authors.initials: JR
authors.lastname: Diers
authors.forename: David F
authors.initials: DF
authors.lastname: Bocian
authors.forename: Dewey
authors.initials: D
authors.lastname: Holten
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lindsey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
mesh_terms: D000890:Anti-Infective Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D008027:Light; D018613:Microscopy, Confocal; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000890:Anti-Infective Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; C452433:bacteriochlorin