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Review
.2023 Nov 20;12(22):2664.
doi: 10.3390/cells12222664.

Chromophore-Targeting Precision Antimicrobial Phototherapy

Affiliations
Review

Chromophore-Targeting Precision Antimicrobial Phototherapy

Sebastian Jusuf et al. Cells..

Abstract

Phototherapy, encompassing the utilization of both natural and artificial light, has emerged as a dependable and non-invasive strategy for addressing a diverse range of illnesses, diseases, and infections. This therapeutic approach, primarily known for its efficacy in treating skin infections, such as herpes and acne lesions, involves the synergistic use of specific light wavelengths and photosensitizers, like methylene blue. Photodynamic therapy, as it is termed, relies on the generation of antimicrobial reactive oxygen species (ROS) through the interaction between light and externally applied photosensitizers. Recent research, however, has highlighted the intrinsic antimicrobial properties of light itself, marking a paradigm shift in focus from exogenous agents to the inherent photosensitivity of molecules found naturally within pathogens. Chemical analyses have identified specific organic molecular structures and systems, including protoporphyrins and conjugated C=C bonds, as pivotal components in molecular photosensitivity. Given the prevalence of these systems in organic life forms, there is an urgent need to investigate the potential impact of phototherapy on individual molecules expressed within pathogens and discern their contributions to the antimicrobial effects of light. This review delves into the recently unveiled key molecular targets of phototherapy, offering insights into their potential downstream implications and therapeutic applications. By shedding light on these fundamental molecular mechanisms, we aim to advance our understanding of phototherapy's broader therapeutic potential and contribute to the development of innovative treatments for a wide array of microbial infections and diseases.

Keywords: endogenous chromophores; photoinactivation of catalase; phototherapy; staphyloxanthin photolysis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Photoinactivation of catalase sensitizes bacteria to exogenous sources of reactive oxygen species (ROS). (A) Molecular structure of catalase. Catalase contains four iron-containing heme groups that act as an active site for the breakdown of H2O2. (B) Transient absorption imaging of bovine liver catalase captured at a pump/probe wavelength of 410/520 nm through a time-course manner. (C) Real-time recording of catalase photoinactivation based on the signals in panel (B). The resulting catalase decay curve is fitted under a second-order photobleaching model. (D) Remaining catalase activity from bovine liver catalase following treatment with 15 J/cm2 of varying wavelengths of blue light. Treatment with 410 to 420 nm of light resulted in a 50% reduction in catalase activity. (E) Resonance Raman spectroscopy of bovine liver catalase treated with 30 J/cm2 of 410 nm blue light. Raman peaks corresponding to catalase (754 cm−1) disappear following treatment. (F) Schematic illustration demonstrating the increased ROS sensitization induced by catalase photoinactivation in catalase-positive bacteria strains. (G–I) Colony-forming unit (CFU) assays of various pathogens treated with 410 nm light and incubated with 22 mM of H2O2 for 30 min. (J) CFU assay ofE. coli BW25113 treated with 410 nm light and silver sulfadiazine. (K) CFU assay of the catalase deficientE. coli ΔkatGE mutant treated with 410 nm light and silver sulfadiazine. In the catalase-deficient mutant, light had no impact on silver sulfadiazine performance. (L–O) Confocal images of intracellular live (SYTO 9) and dead (PI) MRSA inside RAW264.7 macrophages without (L,M) and with (N,O) 410 nm treatment. #: below the detection limit. ****:p < 0.0001. ***:p < 0.001. ns—not significant. Panels (A–I andL–O) alongside panels (J,K) were adapted from papers [61,62] with the authors’ permission, respectively.
Figure 3
Figure 3
Catalase photoinactivation sensitizes fungal pathogens to exogenous sources of ROS and suppressesCandida hyphae development. (A) Remaining catalase activity from variousCandida fungal species following treatment with 15 J/cm2 of 410 nm blue light. (B) Time-killing assay of wild-typeC. albicans SC5314 treated with 30 J/cm2 of 410 nm blue light incubated alongside 11 mM of H2O2 in yeast extract-peptone-dextrose (YPD) broth. CFU/mL was quantified over the course of 4 h. (C) CFU/mL assay ofC. auris 1 strain treated with 36 J/cm2 of 410 nm light and various concentrations of H2O2 for 4 h. The addition of light significantly improved H2O2 activity againstC. auris. (D) CFU/mL values ofC. auris 1 strain derived from a PrestoBlue proliferation assay and calibration curve.C. auris was treated with 30 J/cm2 of blue light and incubated with varying concentrations of amphotericin B or fluconazole. (E) Phase contrast imaging of untreatedC. albicans SC5314 following 1 h incubation under hyphae-forming conditions. (F) Phase contrast imaging ofC. albicans SC5314 treated with 60 J/cm2 of 410 nm light following 1 h incubation under hyphae-forming conditions. (G) Histogram of untreated versus blue-light-treatedC. albicans hyphae. Light treatment significantly reduces average hyphae length. #: below the detection limit. **:p < 0.01; ***:p < 0.001. Panels (A–G) were adapted from papers [78,79] with the respective authors’ permission.
Figure 4
Figure 4
Characterization of morphology and ultrastructure of the bacteria and bacterial biofilms in response to reactive oxygen species (ROS) generated from endogenous porphyrins and catalase under blue light irradiance. (A) Representative images from transmission electron microscopy illustrating aBL-inducing ultrastructural damage inP. aeruginosa andS. aureus. Red asterisk, agglutination of intracellular contents; black asterisk, cell wall/membrane damage; white arrow, leakage of intracellular contents; red arrow, membrane destabilization. Scale bar: 500 nm. Abbreviations: LD90 and LD99.9, lethal doses responsible for 90% and 99.9% killing, respectively. (B) Fluorescence lifetime imaging (FLIM) images of endogenous fluorophores fromP. aeruginosa (a to c) andS. aureus (e to g). Different colors represent different fluorescence lifetimes for each bacterial species (green, blue, red). (C) The SEM images show the morphology and ultrastructure of the bacterial biofilms after various treatments. Treatments: aBL + quinine, aBL, Quinine, or untreated control. Black arrows: biofilm matrix. Scale bar: 500 nm. (D) Schematic summary of the interactions between photons and two primary intrinsic photosensitive chromophores within microbes. Panels (A–C) were adapted from papers [95,96] with the respective authors’ permission.
Figure 1
Figure 1
Characterization of the mechanisms and antimicrobial applications of pigment photolysis. (A) Transient absorption imaging of MRSA acquired at a pump/probe wavelength of 520/780 nm detected a strong initial signal associated with the staphyloxanthin (STX) chromophore at the initial time t = 0 s. The signal decayed within a second of exposure. (B) Representative time-lapse STX signal in MRSA. MRSA intensity was fitted to a second-order photobleaching model. (C) Digital images of concentrated MRSA droplets under the treatment of 460 nm blue light. Over the course of 4 min of light exposure, the golden yellow coloration in MRSA fades. (D) Resonance Raman spectroscopy of MRSA samples treated with pulsed blue light. Raman peak positions (labeled by wavenumber) associated with STX decrease with light exposure. (E) Theorized structural breakdown of STX following exposure to 460 nm light. (F) Comparison of the STX photolysis kinetics within MRSA treated under either continuous-wave light-emitting diode (LED) or a nanosecond pulsed laser at 460 nm under the same power conditions. The black curve on the pulsed data represents the fitting result under a second-order photobleaching model. (G) Time-killing assay of MRSA resuspended in phosphate-buffered saline (PBS) for up to 8 h following exposure to varying dosages of 460 nm light. (H) Schematic of the mechanisms behind the resensitization of conventional antibiotics in MRSA following treatment with pulsed blue light. Pore formation induced by STX photolysis of membrane microdomains disrupts pre-existing resistance mechanisms. (I) Quantitation of uptake of FD70 in MRSA by fluorescence following pulsed light treatment. (J) Characterization of resistance development of untreated and light-treated MRSA over the course of a 48-day serial passage in the presence of sub-minimum inhibitory concentration (MIC) levels of ciprofloxacin. No resistance development occurred with light-treated MRSA. (K) Digital image profile of concentratedS. agalactiae following exposure to 120 J/cm2 of pulsed 430 nm blue light. Over the course of light treatment, the orange associated with the granadaene pigments fades to white. ***:p < 0.001. **:p < 0.01. ns—not significant. Panels (A–K) were adapted from papers [37,42] with the respective authors’ permission.
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