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Review
. 2020 Jan 31;9(2):53.
doi: 10.3390/antibiotics9020053.

Oxygen-Independent Antimicrobial Photoinactivation: Type III Photochemical Mechanism?

Michael R Hamblin  1   2   3 , Heidi Abrahamse  3
Affiliations
Review

Oxygen-Independent Antimicrobial Photoinactivation: Type III Photochemical Mechanism?

Michael R Hamblin et al. Antibiotics (Basel). .

Abstract

Since the early work of the 1900s it has been axiomatic that photodynamic action requires the presence of sufficient ambient oxygen. The Type I photochemical pathway involves electron transfer reactions leading to the production of reactive oxygen species (superoxide, hydrogen peroxide, and hydroxyl radicals), while the Type II pathway involves energy transfer from the PS (photosensitizer) triplet state, leading to production of reactive singlet oxygen. The purpose of the present review is to highlight the possibility of oxygen-independent photoinactivation leading to the killing of pathogenic bacteria, which may be termed the "Type III photochemical pathway". Psoralens can be photoactivated by ultraviolet A (UVA) light to produce DNA monoadducts and inter-strand cross-links that kill bacteria and may actually be more effective in the absence of oxygen. Tetracyclines can function as light-activated antibiotics, working by a mixture of oxygen-dependent and oxygen independent pathways. Again, covalent adducts may be formed in bacterial ribosomes. Antimicrobial photodynamic inactivation can be potentiated by addition of several different inorganic salts, and in the case of potassium iodide and sodium azide, bacterial killing can be achieved in the absence of oxygen. The proposed mechanism involves photoinduced electron transfer that produces reactive inorganic radicals. These new approaches might be useful to treat anaerobic infections or infections in hypoxic tissue.

Keywords: antimicrobial photodynamic inactivation; bacteria; oxygen-independent photoinactivation; potassium iodide; psoralens; sodium azide; tetracyclines.

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Conflict of interest statement

M.R.H. declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE.

Figures

Figure 1
Figure 1
Jablonski diagram. Illustrating Type I electron transfer pathway producing superoxide, hydrogen peroxide, and hydroxyl radicals, and Type II energy transfer pathway producing singlet oxygen.
Figure 2
Figure 2
DNA cross-linking by photoactivated psoralens. Example shown is 8-methoxypsoralen forming either a 3,4-mono-adduct or else a 4’,5’-monoadduct with a thymine base. These mono-adducts can absorb a second ultraviolet-A (UVA) photon and form an inter-strand cross-link with a second thymine base in the opposite strand.
Figure 3
Figure 3
Amotosalen structure. 3-(2-aminoethoxymethyl)-2,5,9-trimethylfuro[3,2-g] chromen-7-one HCl.
Figure 4
Figure 4
Tetracycline structures. (A) Doxycycline hydrochloride (DOTC); (B) Demeclocycline hydrochloride (DMCT).
Figure 5
Figure 5
Oxygen-independent bacterial photoinactivation mediated by tetracyclines. Bacterial cells (E. coli or MRSA 10(8) CFU/mL) were incubated with tetracyclines (DOTC or DMCT, 100 µM) for 30 min with or without addition of sodium azide (50 mM), and either in air or bubbled with N2/Ar. At the end of incubation 10 J/cm2 of UVA (DOTC) or blue (415 ± 15 nm) light (DMCT) was delivered. Values are calculated based on no treatment control. Reproduced from [51] (open access).
Figure 6
Figure 6
Oxygen-independent bacterial killing mediated by MB plus potassium iodide. (A) Structure of MB. (B) Antimicrobial effect of MB (0.4 μM) with or without KI (100 mM) plus 6 J/cm2 660 nm light against E. faecalis planktonic cells in presence and absence of oxygen (anaerobic incubator). Reproduced with permission from [69]; Copyright Elsevier.
Figure 7
Figure 7
Oxygen-independent bacterial killing mediated by MB plus sodium azide. Bacteria (10(8) cells/mL) were incubated with MB for 30 min and then with addition or not of NaN3 (100 µM), followed by removal or not of oxygen by bubbling with nitrogen, and illumination with up to 8 J/cm2 of 660-nm light. (A) S. aureus and 100 µM MB in oxygen; (B) S. aureus and 100 µM MB in nitrogen; (C) E. coli and 200 µM MB in oxygen; (D) E. coli and 200 µM MB in nitrogen. Reproduced with permission from [56]; Copyright Elsevier.
Figure 8
Figure 8
Structures of polycationic functionalized fullerenes. LC14 has two chains each of five quaternized nitrogen groups, making it decacationic. LC15 has a similar arrangement of two chains of 5 quaternized nitrogens, but this time attached to a light-harvesting antenna called CPAF. LC16 has two chains of 5 quaternized nitrogens, but in addition has two additional chains of 5 tertiary nitrogens (ten in all).
Figure 9
Figure 9
Oxygen-independent bacterial killing mediated by fullerenes and sodium azide. Bacteria (10(8) cells/mL) were incubated with fullerene compounds at 10 µM for 1 hour, followed by exposure to increasing fluences of while light (400–700 nm). aPDI was carried in the presence or absence of sodium azide (10 mM) and in the presence or absence of oxygen (75% N2/25% Ar). (A) MRSA + LC14; (B) MRSA + LC15; (C) MRSA + LC16; (D) E. coli + LC14; (E) E. coli + LC15; (F) E. coli + LC16. Adapted from data in [74].
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