A drug-free approach for inactivating pathogenic

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Antimicrobial blue light: a drug-free approach for inactivating pathogenic microbes

Ying Wang, Tianhong Dai

Ying Wang, Tianhong Dai, "Antimicrobial blue light: a drug-free approach for inactivating pathogenic microbes," Proc. SPIE 10479, Light-Based Diagnosis and Treatment of Infectious Diseases, 104790J (8 February 2018); doi: 10.1117/12.2283019 Event: SPIE BiOS, 2018, San Francisco, California, United States Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 6/30/2018 Terms of Use: https://www.spiedigitallibrary.org/terms-of-use

Invited Paper

Antimicrobial blue light: A drug-free approach for inactivating pathogenic microbes Ying Wanga,b, Tianhong Dai*a a

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, USA 02114 b Department of Laser Medicine, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China, 100853

ABSTRACT Due to the growing global threat of antibiotic resistance, there is a critical need for the development of alternative therapeutics for infectious diseases. Antimicrobial blue light (aBL), as an innovative non-antibiotic approach, has attracted increasing attention. This paper discussed the basic concepts of aBL and recent findings in the studies of aBL. It is commonly hypothesized that the antimicrobial property of aBL is attributed to the presence of endogenous photosensitizing chromophores in microbial cells, which produce cytotoxic reactive oxygen species upon light irradiation. A wide range of important microbes are found to be susceptible to aBL inactivation. Studies have also shown there exist therapeutic windows where microbes are selectively inactivated by aBL while host cells are preserved. The combination of aBL with some other agents result in synergistically improved antimicrobial efficacy. Future efforts should be exerted on the standardization of study design for evaluating aBL efficacy, further elucidation of the mechanism of action, optimization of the technical parameters, and translation of this technique to clinic. Keywords: Antimicrobial blue light, antibiotic-resistance, microbes, host cells, combination therapy, mechanism of action, endogenous photosensitizers, reactive oxygen species.

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405 nm: peak antimicrobial activity via photo- excitation of endogenous porphyrins; oxidative damage Figure 1. Spectrum of visible light

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[email protected]; phone 1 617 726 6169; fax 1 617 726 6643; https://connects.catalyst.harvard.edu/Profiles/display/Person/9131

Light-Based Diagnosis and Treatment of Infectious Diseases, edited by Tianhong Dai, Proc. of SPIE Vol. 10479, 104790J · © 2018 SPIE · CCC code: 1605-7422/18/$18 · doi: 10.1117/12.2283019

Proc. of SPIE Vol. 10479 104790J-1 Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 6/30/2018 Terms of Use: https://www.spiedigitallibrary.org/terms-of-use

1. WHAT IS ANTIMICROBIAL BLUE LIGHT? Light is electromagnetic radiation that can be detected by human eye. Violet/blue light, which covers the spectrum from 400 to 470 nm wavelengths (Figure 1), is intrinsically antimicrobial possibly attributed to the presence of the naturally occurring endogenous photosensitizing chromophores (i.e., photosensitizers) in microbial cells.1, 2 The endogenous photosensitizers absorb violet/blue light and subsequently lead to the production of cytotoxic reactive oxygen species (ROS) that can inactivate microbes. In the Biomedical Optics and Infectious Disease societies, violet/blue light is also termed antimicrobial blue light (aBL) when it is applied in the inactivation of microbes.

2. WHAT IS THE IMPORTANCE LYING IN THE STUDIES OF ANTIMICROBIAL BLUE LIGHT AS AN ALTERNATIVE TO TRADITIONAL ANTIBIOTICS? Although microbiologists have been ringing the alarm bell for years, the threat of antibiotic resistance in healthcare and community settings has reached new prominence in the popular press that the issue should be added to the list of global emergencies. It is now indisputable that antibiotic resistance is life-threatening in the same sense as cancer, both in the number of cases and the likely outcome.3 According to a recent report released by the Centers for Disease Control and Prevention (CDC), each year in the United States, over 2 million people acquire serious antibiotic resistant infections.4 At least 23,000 people die each year as a direct result of antibiotic resistant infections.4 Many more die from other conditions that are complicated by an antibiotic resistant infection. In addition, antibiotic resistant infections add considerable and avoidable costs to the already overburdened United States healthcare system. In most cases, antibiotic resistant infections require prolonged and/or costlier treatments, extend hospital stays, necessitate additional doctor visits and healthcare use, and result in greater morbidity and mortality compared with infections that are easily treatable with antibiotics. The estimated total economic cost of antibiotic resistance to the United States economy have ranged as high as $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year.4 The extensive use of antibiotics is the single most important factor leading to antibiotic resistance.4, 5 There is, subsequently, a pressing need for the development of alternative treatment regimens for antibiotic-resistant infections. Recently, Dr. Karen Bush and 29 other experts in antibiotic resistance noted in Nature Reviews Microbiology that: ″The investigation of novel non-antibiotic approaches for the prevention of and protection against infectious diseases should be encouraged, and such approaches must be high-priority research and development projects.″3 Antimicrobial blue light (aBL), as a non-antibiotic approach, has attracted increasing attention due to its intrinsic antimicrobial property. The potential applications of aBL cover not only the treatment of infectious diseases but also environmental sterilization,6, 7 postharvest preservation,8-15 veterinary medicine,16 etc.

3. WHAT ARE THE MAJOR ADVANTAGES OF ANTIMICROBIAL BLUE LIGHT OVER OTHER ANTIMICROBIALS? aBL is compelling in that it is a non-antibiotic approach that is non-injurious to host cells and tissues. In comparison to antimicrobial photodynamic therapy, aBL inactivates microbes without the involvement of exogenous photosensitizers. It is also well accepted that aBL is much less detrimental to host cells than germicidal ultraviolet C (UVC) irradiation.1718 In addition, aBL exhibits equal inactivation effectiveness of microbes regardless of their status of antibiotic resistance. Furthermore, it is envisioned that microbes are less able to develop resistance to aBL than to traditional antibiotics, because of the multi-target feature of aBL.2


4. WHAT IS THE MECHANISM OF ACTION OF ANTIMICROBIAL BLUE LIGHT? The mechanism of action of aBL is still not fully understood although significant efforts have been exerted in further elucidating it in recent years. The common hypothesis is that aBL excites the naturally occurring endogenous photosensitizers in microbial cells, and subsequently leads to the production of ROS that can inactivate microbes (Figure 2). The studies using the DNA manipulation technique support this hypothesis.19, 20 The endogenous photosensitizers, including porphyrins, flaviins, and/or NA ADH, have been successfullyy identified inn some importaant microbes.1, 2, 19, 21-34 d the evidencess that aBL inacctivation of miccrobes is attribbuted to ROS-iinduced cell membrane Studies have also provided 1 26, 28, 29, 35-39 ulence factors, DNA-oxidatioon, and geneticc changes, etc.19, damage, inacctivation of viru

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Figure 2. 2 Mechanism of action of antim microbial blue ligght

5. WHAT W ARE E THE CURR RENT FOCU USES IN THE STUDIES OF ANTIM MICROBIAL BL LUE LIGHT T? At present, aBL a studies aree focused on thhe efficacy of aBL inactivatiion of differennt microbes, itss mechanism of o action, synergism off aBL with oth her agents, its effect on host cells and tissuues, and the pootential develoopment of resisstance to aBL by micrrobes. A widee range of miccrobial speciess has been testted for aBL innactivation, including Gram--positive bacteria, Graam-negative baacteria, mycobbacteria, moldss, yeasts, and dermatophytess.1, 2 Although varying resultts of the aBL efficacyy have been observed in diffeerent studies duue to the varyinng conditions, the majority of o the microbess studied have been fouund to be susceeptible to aBL inactivation. 1, 2, 39 Animal studiies have demo onstrated that aBL a can signifficantly reducee microbial loaad in infected lesions, indicaating the potency of aBL a for infectious diseases.222-25, 40-43 Two pilot p clinical sttudies showed the effectivenness of aBL inn treating dental pathoggens.44, 45 In sev veral ongoing studies of our laboratory, wee are testing aB BL therapy for urinary tract innfections, genital tract infections, i imp plant-related infections, and open o fracture innfections in muurine models. The synergisstic antimicrobiial effect of aB BL with other agents (such as a antibiotics, disinfectants, d extracts from medicinal m plants, nanopparticles, ultrassound, etc.) hass been reportedd by several stuudies.46-49 2 40, 50 As a safety study s of aBL application, thhe effect of aB BL on host cellls and tissues has also beenn investigated,22-25, including cyytotoxicity and d genotoxicity.. Those studiees have suggeested that therre exist therappeutic window ws where microbes aree selectively in nactivated while host cells aree preserved.23-225, 40, 50 In adddition, no evideence of genotoxicity of aBL is observved in mouse skin s in vivo whhen exposed too the therapeutiic aBL exposurre for inactivatting mature bioofilms in vivo.22


6. WHA AT SHOULD D BE DONE IN THE FUT TURE IN TH HE STUDIES S OF ANTIMICR ROBIAL BLU UE LIGHT? Future efforts should be exerted on the standardization of the study conditions for investigating the efficacy of aBL, further elucidation of the mechanism of action, optimization of the technical parameters, and translation of this technique to clinic.

ACKNOWLEDGEMENTS The research in TD group has been supported by the National Institute of Health (R21AI109172 and R01AI123312 to TD).

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