Stable synthetic cationic bacteriochlorins as selective antimicrobial photosensitizers.
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.
Huang
Liyi
L
Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114-2696, USA.
Huang
Ying-Ying
YY
Mroz
Pawel
P
Tegos
George P
GP
Zhiyentayev
Timur
T
Sharma
Sulbha K
SK
Lu
Zongshun
Z
Balasubramanian
Thiagarajan
T
Krayer
Michael
M
Ruzié
Christian
C
Yang
Eunkyung
E
Kee
Hooi Ling
HL
Kirmaier
Christine
C
Diers
James R
JR
Bocian
David F
DF
Holten
Dewey
D
Lindsey
Jonathan S
JS
Hamblin
Michael R
MR
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
D000890:Anti-Infective Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; C452433:bacteriochlorin