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The World Health Organization has classified the threat of antimicrobial resistance as one of the major threats to human health worldwide. New strategies and ideas are of interest to prevent spread and to control antibiotic‐resistant bacteria. Currently cold atmospheric plasma and the photodynamic principle using photoantimicrobials can be mentioned as two new innovative state of the art techniques for successful eradication of bacteria. Here in this review an update is given about the current status of the photodynamic principle and new developments of photoantimicrobials. This article is protected by copyright. All rights reserved.
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REVIEW
PhotoantimicrobialsAn update
Tim Maisch
Department of Dermatology, University
Medical Center Regensburg, Regensburg,
Germany
Correspondence
Tim Maisch, Department of Dermatology,
University Medical Center Regensburg,
Franz-Josef-Strauß-Allee 11, 93053
Regensburg, Germany.
Email: tim.maisch@klinik.uni-
regensburg.de
Abstract
The World Health Organization has classified
the threat of antimicrobial resistance
as one of the major threats to human
health worldwide. New strategies and
ideas are of interest to prevent spread
and to control antibiotic-resistant
bacteria. Currently cold atmospheric
plasma and the photodynamic princi-
ple using photoantimicrobials can be
mentioned as two new innovative
state of the art techniques for successful eradication of bacteria. Here in this
review an update is given about the current status of the photodynamic princi-
ple and new developments of photoantimicrobials.
KEYWORDS
light-activated antimicrobial surface, photoantimicrobials, photodynamic, potentiation
1|INTRODUCTION
In 2016 the Jim O'Neill report summarized that in 2050
more people will die by infections caused by multiresistant
pathogens than by tumors based on an extrapolation of
the current data of antimicrobial resistance (AMR) [1].
Furthermore there is a reverse development of new antibi-
otics vs resistant bacteria [2]. That means developments of
new technologies are needed to combat multiresistant
pathogens. However, such new technologies should not
exchange an antibiotic treatment, but moreover helping to
reduce the load of pathogens in patients. Update informa-
tion about AMR is given elsewhere [3, 4]. Currently two
new state of the art technologies are under investigation or
already in clinical practice, namely the antimicrobial pho-
todynamic process and cold atmospheric plasma (CAP)
[57]. Both technologies are able to inactivate successful
multiresistant pathogens, like the ESKAPE pathogens as
well as fungi and virus. The so called ESKAPEpatho-
gens enclose all highly multidrug or extended,- and pan,-
drug resistant bacteria strains worldwide such as
vancomycin-resistant Enterococcus faecium; methicillin-
resistant Staphylococcus aureus and the multi-drug resis-
tant species Klebsiella pneumoniae,Acinetobacter
baumannii,Pseudomonas aeruginosa and Enterobacter
ssp. [811]. Currently these species provoke a large num-
ber of infections with limited therapy options.
CAP is a contact-free application which is ionizing
ambient air by, for example, surface micro-discharge
plasma technology, thereby generating a reactive cocktail
of radicals, ions, electrons and photons. Currently CAP is
already used in clinical practices for treatment of super-
infected wounds [12]. However, the focus of this review
will be on the other new technique the antimicrobial
photodynamic process.The photodynamic process is
characterized by a three-component system
Received: 5 December 2019 Revised: 18 February 2020 Accepted: 24 February 2020
DOI: 10.1002/tbio.201900033
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2020 The Author. Translational Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Translational Biophotonics. 2020;2:e201900033. www.tbio-journal.org 1of9
https://doi.org/10.1002/tbio.201900033
(photoantimicrobial dye, oxygen and light of appropriate
wavelengths), at which the photoantimicrobial dye is acti-
vated by visible light (wavelengths range: 380-700 nm),
thereby generating a cocktail of reactive oxygen species
depending if type-I or type-II mechanism of action occurs
[13, 14]. Briefly, in a type-I mechanism of action, electrons
are transferred from the excited state of a light-activated
photoantimicrobial to oxygen, whereas in a type-II mecha-
nism of action onlyenergy is transferred from the
excited light-activated photoantimicrobial to oxygen,
though the highly reactive singlet oxygen is produced.
Currently photoantimicrobial dyes acting via type-II mech-
anism, that means generating predominantly singlet oxy-
gen are of interest due to the point that bacterial defense
strategies are aligned against oxidative stress in form of
oxygen radicals [1518]. Detailed photobiological, photo-
chemical and photophysical information [1921] as well as
potential applications of photoantimicrobials can be found
elsewhere [2224]. Here in this review an update of pho-
toantimicrobials is given concerning about new pho-
toantimirobial developments, new strategies of
applications, potentiation effect of the photodynamic effect
and combination of the photodynamic effect with
antibiotics.
2|UPDATE OF NEW
PHOTOANTIMICROBIALS
Within the last 10 years a large number of new pho-
toantimicrobials were developed and reported on basis of
different chemical structures of the core-group including
chemical sidechain modifications [14]. The properties of
suitable photoantimicrobials for sufficient killing of
microorganisms is summarized in details elsewhere [25].
Up to now there were developed different chemical clas-
ses of photoantimicrobial. In general these classes are
cyclic tetrapyrroles like porphyrins, phthalocyanines,
chlorins and bacteriochlorins as well as the
phenothiazinium-based photoantimicrobials like
methylene blue or toluidine blue and its derivatives with
excellent performance [2631]. Besides methylene blue,
toluidine blue, phthalocyanines and other tetrapyrrolic
macrocycles new photoantimicrobials were developed
based on a non-porphyrine core-group (Table 1). Table 1
shows a selection of such newly developed pho-
toantimicrobials and its highlights. So far actual each
group of photoantimicrobial has its own merit.
2.1 |Vitamin B2 derivatives
Riboflavin comprises a natural group of pho-
toantimicrobials which have shown generation of ROS
including singlet oxygen when exposed to light.
Recently several research groups demonstrated a photo-
dynamic inactivation of bacteria as well as of viruses
using riboflavin [32, 33]. In these studies the total illu-
mination time was about 8 to 10 minutes or the bacte-
ria were incubated with riboflavin for 2 hours in
presence of light, respectively [32, 33]. Recently Maisch,
Eichner et al. demonstrated that newly synthesized fla-
vin derivatives FLASH-01a and FLASH-07a containing
one or eight positives charges was effective in killing
multi-drug resistant bacteria including MRSA, EHEC,
Pseudomonas aeruginosa or Acinetobacter baumannii
(Figure 1A) [34]. The results of this study were encour-
aging, because the total treatment time of the photody-
namic process was within 30 seconds up to maximum
180 seconds to achieve an antimicrobial effect compared
to the other studies. This demonstrates that the inser-
tion of positive charges seems to be a must have for a
fast and effective photodynamic effect.
2.2 |Curcumin derivatives
Curcumin is a natural dye extracted from the rhizomes of
Curcuma longa and it is approved as a food additive
E100. Several studies investigated and verified the
TABLE 1 Highlights of new photoantimicrobial developments
Structural core-group
(chemical backbone) Name of photoantimicrobial Highlights References
Riboflavin FLASH-01a, FLASH-07a Positive charges, singlet oxygen
quantum yield of 75%
[34]
Curcumin SACUR Positive charges, core-molecule
curumin approved as E100 food additive
[41]
Phenalenones SAPYR Positive charge, singlet oxygen quantum
yield of ~99%, low molecular weight,
substantial effects on bacterial biofilms
[42]
Triphenylphosphonium TPP Selective killing of Gram-positive bacteria
in presence of Gram-negative
[44]
2of9 MAISCH
antimicrobial photodynamic ability of curcumin due to
its excellent biocompartibility and since curcumin is
already approved as a foodstuff [3540]. Spaeth et al. syn-
thesized cationic and water-soluble curcumin derivatives
to enhance the killing efficacy of light-activated cur-
cumin for its applicability as photoantimicrobials to
decontaminate plant food (Figure 1B) [41].
2.3 |Phenalenones
SAPyR is based on a 7-perinaphthenone core structure
containing a positively charged pyridinium-methyl sub-
stituent [42]. Originally the water-soluble peri-
naphthenone was investigated by Nonell et al., later on
Cieplik et al. showed that SAPyR induced >99.99% of bio-
film inactivation upon light activation and acting pre-
dominantly via type-II, the quantum yield of singlet
oxygen generation averaged >98% (Figure 1C) [42, 43].
2.4 |Triphenylphosphonium-based
photoantimicrobials
Currently the research focus in antimicrobial photody-
namic inactivation was to kill very efficiently (>99.999%
killing efficacy; means disinfection) all kinds of bacteria
independently of its antibiotic resistance background.
This raised the question of whether it would be possible a
selective killing of Gram-positive bacteria in presence of
Gram-negative bacteria? This question was answered by
Bresoli-Obach et al., which demonstrated a selective kill-
ing of Gram-positive bacteria but not of Gram-negative
when triphenylphosphonium as the functional group was
attached to different chemical photoantimicrobials [44].
The authors of this study mentioned that such
triphenylphosphonium based photoantimicrobials might
be of interest in a clinical situation where selective eradi-
cation of Gram-positive bacteria in the presence of Gram-
negative pathogens seems to be a therapeutic issue,
where it is necessary to kill bad bugs, but to preserve the
commensal microflora (Figure 1D & E) [44].
3|POTENTIATION EFFECT OF
THE ANTIMICROBIAL
PHOTODYNAMIC PROCESS
3.1 |Ultrasound
One limitation of the antimicrobial photodynamic effect
is that visible light is penetrated partial insufficiently
FIGURE 1 Chemical structures of photoantimicrobials. A, Flash-01a (Vitamin B2 derivative); B, 4-fold positive charged curcumine; C,
SAPyR; D, Triphenylphosphonium; E, Triphenylphoshonium bound to phenalenone core structure. The corresponding counterions are Cl
or Br
MAISCH 3of9
through human tissue, thereby reducing its effectiveness
when used to treat super-infected deep-seated infections.
An adjuvant to enhance penetration in deeper human tis-
sue (up to 10 cm) seem to be ultrasound. Several groups
could demonstrate a positive anti-tumor effect of ultra-
sound and a given photosensitizers in animal models
in vivo [4548]. Costely et al. investigated the ability of
low-intensity ultrasound to enhance uptake of a rose-
bengal conjugated with an antimicrobial peptide, as the
given photosensitizer, in bacterial biofilms and human
tissue [49]. It was demonstrated, that ultrasound treated
infected in vivo wounds incubated with such a rose-ben-
gal-antimicrobial peptide affects a reduction of bacterial
burden. The authors of this study concluded, that ultra-
sound in combination with the antimicrobial photody-
namic process might be a new modality for the treatment
of deep-seated bacterial infections in the future [49].
3.2 |Azide and other inorganic salts
It is generally known that sodium azide (Na
+
N
3
) acts as
a quencher of ROS, especially for singlet oxygen during
photodynamic treatments [50, 51]. Surprisingly Huang
et al. demonstrated a potentiation of the photodynamic
effect in present of azide ions, when bacteria were incu-
bated with methylene blue and illuminated, for the first
time [52]. The authors of this study concluded, that such
a potentiating effect of azide on bacterial killing induced
by Fenton reaction could be explained by an one-electron
oxidation of hydroxyl radicals to azidyl radicals. Further-
more they found that the azidyl radical is also formed in
absence of oxygen by one-electron oxidation of the azide
anion by photoexcited methylene blue. Overall this new
observation of azidyl radicals generation by photoexcited
photoantimicrobials in present of azide anions might be
a possibility for bacterial inactivation where oxygen con-
centration is limited. In addition other research groups
demonstrated such a potentiation effect likewise by using
iodide ions [5358]. An excellent overview about the cur-
rent knowledge of the potentiation effect of inorganic
salts when added to photoantimicrobials during light
activation is given elsewhere [59].
3.3 |Combination of antimicrobial
agents and photoantimicrobials
It is generally accepted that the mechanism of action of
photoantimicrobials is independent of the antibiotic
resistance status of a given pathogen and is thought
unlikely to induce/produce a resistance like bacteria can
do it against an antibiotic. So far there are some clinical
isolates showing a higher tolerance against photo-
antimicrobial inactivation compared to the wildtype
strain, but no resistance [8, 60]. Therefore He et al. inves-
tigated the possibility whether tetracyclines could medi-
ate on the one hand a photodynamic inactivation during
illumination and on the other an antibiotic action in the
dark to prevent bacterial regrowth by inhibiting the 30s
subunit of ribosomes and yet inhibiting the binding of
aminoacyl-tRNA to the mRNA translation complex [61].
Such dual-action light-activated antibioticscould be a
new strategy in the future by combing to different mecha-
nisms of action of different antimicrobial techniques for
efficient inactivation of multiresistant pathogens. Indeed
it is known, that tetracyclines can induce a major pho-
tosensibilization in vivo as side effect in some patients
[62, 63]. Therefore such a combined application in clinic
settings seems to be critical. However, critical discussions
about both single and combined effects of photodynamic
action and antibiotics as well as the current status of
combination of photoantimicrobials together with anti-
microbial agents are given elsewhere [64, 65].
4|PHOTODYNAMIC ACTIVE
ANTIMICROBIAL SURFACES
Transmission of pathogens from inert surfaces in clinical
environment to patients and vice versa plays an impor-
tant role for the spread of nosocomial infections in the
clinic [24, 66, 67]. Many pathogens can survive on inert
surfaces for several months and remain infectious [68].
These pathogens form a kind of an infectious reservoir;
in case contaminated surfaces were not sufficiently often
and reliably disinfected. There are known a few strategies
for antimicrobial surfaces: (a) a polymer is coated with
the loaded antimicrobial biocide, thereby a release of
time of the biocide itself takes place (eg, Ag
+
ion coated
surfaces [69]); or (b) polymer surface modifications that
either kills bacteria or prevent bacteria absorption (eg,
quaternary ammonium compounds coated surfaces) [70].
About 10 years ago Decraene et al. investigated the
potential of light-activated antimicrobial coatings to
reduce the microbial load on such surfaces [71]. In this
study cellulose acetate coatings embedded with toluidine
blue O or rose Bengal as the appropriate pho-
toantimicrobials were used. The results of this study
showed, that a significant reduction of CFU of S. aureus
applied on this coating is possible when irradiated by a
domestic light source [71]. This study encouraged
research investigations to develop light-activated coatings
to reduce microbial contamination of inert surfaces in
hospitals. Recently, a new antimicrobial coating based on
photodynamicswas developed by Eichner et al. [72].
4of9 MAISCH
Such new photodynamic coatings consist of a special
photoantimcirobial molecule, which is not visible to the
human eye and therefore not changing the color of the
surface. These photoantimicrobial generates reactive oxy-
gen species upon activation by, for example, room light
systems. The results of this proof of concept study by
Eichner et al. demonstrated for the first time, that the
bacterial load was significantly lower on photodynamic
surfaces compared to control surfaces in clinical daily
routine [72]. The authors of this study concluded, that
such photodynamic coatings reduce colonization of bac-
teria on inert surfaces and minimize the risk of possible
transmission of pathogens, thus making an important
step toward improved patient safety [72]. Furthermore
Hu et al. summarized the current knowledge of antimi-
crobial photodynamic therapy to control clinically rele-
vant biofilm infections [22]. Whereas in addition Spagnul
et al. described the concept of using photosensitizers
immobilized on a solid surface as a potential promising
alternative to address a range of economic, ecological and
public health issues [24].
5|APPLICATIONS OF THE
PHOTODYNAMIC PROCESS BASED
ON NATURAL
PHOTOANTIMICROBIALS AGAINST
PLANT PATHOGENS
In view of the growing world population arises more and
more the problem that possible contamination of food
with germs during production and storage can no longer
guaranteed a safe and adequate supply of food for every-
one in the future [73]. More than ever contamination of
food throughout the food production chain by microor-
ganisms can pass always not only in poor countries but
also in industrial countries [74]. Therefore, the interest in
new ideas like the photodynamic decontamination of
microbial contaminated food has become into focus in
recent years. Possible applications of the photodynamic
process in microbial food safety are as follows [75]:
Natural-derived photoantimicrobials like curcumins
against plant pathogens directly during plant,-fruit,-
crop growth to increase the crop harvest
Photodynamic application during food processing to
reduce preexisting contamination on food and to
improve hygiene condition during processing
Photodynamic application during distribution of food
like antimicrobial photodynamic active wrapping
Input of the photodynamic process during food prepa-
ration to improve hygiene condition
(adopted and modified from Glueck [76].)
6|KEY FEATURES OF AN
ANTIMICROBIAL PHOTODYNAMIC
SYSTEM
Altogether a set of several new photoantimicrobials were
developed within the last 10 years, which demonstrated
excellent antimicrobial photodynamic efficiencies against
different bacterial species. Table 2 shows the must have
key features of a perfectantimicrobial photodynamic
TABLE 2 Must have key features of an antimicrobial photodynamic system
Key feature Description
Structure of the core group Positive charge(s) of the used photoantimicrobial for a high affinity for attachment and
uptake toward the negatively charged bacteria cell walls especially by Gram-negative
bacteria
Hydrophilicity of the used photoantimicrobial for solubility, attachment, penetration and
uptake in combination with a suitable pharmacological formulation
Low-molecular weight for facilitating penetration through biofilm structures and uptake by
bacteria (eg, >600 Da exclusion size for passive penetration through cell wall/membrane
areas of bacteria
Using the concept of click chemistry to speed up the process of photoantimicrobials
synthesis from smaller units by utilizing a few practical and reliable reactions
Singlet quantum yield High
1
O
2
quantum yield, reaction according to type II mechanism to avoid induction of
tolerance by bacteria due to the fact, that type I induced oxygen radicals can be quenched by
bacteria though expression of Superoxid-dismutase and katalase [16], [86]
Photostability High-photostability during irradiation or even degradation possible to avoid
photosensitization after treatment depending on the application
Therapeutic window”•Determination of an effective concentration range (including appropriate light doses), where
microorganisms can be killed sufficiently without damage of eukaryotic cells [19]
Source: Data adopted and modified from Cieplik et al. [5].
MAISCH 5of9
system based on a critical review by Cieplik et al. [5].
Nevertheless a perfectantimicrobial photodynamic sys-
tem does have as well some limitations like insufficient
uptake/attachment of the photoantimicrobials by the
bacteria and thereby causing a deficient killing efficacy.
Therefore some new strategies for optimization were
investigated so far, which are only listed here, because an
excellent detailed discussion can be found in the review
by Liu et al. [77]: (a) conjugation of cationic antimicro-
bial peptides to photoantimicrobials like buforin,
magainin and apidaecin [7880]; (b) efflux pump inhibi-
tors in combination with photoantimicrobials to enhance
the overall toxicity [81, 82]; (c) liposomal photo-
antimicrobial delivery systems can be used to achieve a
better uptake to the target structures, here the cell mem-
brane of bacteria, and also a more controlled release of
the active photoantimicrobial by such a system [8385];
(d) the optimal light source must have a suitable spec-
trum because only such photons can be absorbed by the
photoantimicrobial, if both the emission and absorption
spectra coincide [86]. As a further point in terms of light
source optimization, the following should be mentioned:
The use of up converting nanoparticles that can absorb
photons of the near-infrared wavelengths (~980 nm) to
enhance the photodynamic effect [87].
7|SUMMARY
In November 2019 the Centers for Disease Control and
Prevention (CDC) released the AMR report summarizing
the newest data on antibiotic resistance [88], which
includes the latest national death and infection estimates
that underscore the continued threat of antibiotic resis-
tance in the United States. As a result of AMR pathogens
more than 2.8 million people gained an infection from
these AMR pathogens each year and ~35 000 deaths per
year caused by these superbugs in the United States [88,
89]. In addition Cassini et al. published data about the
deaths and disability-adjusted life-years caused by infec-
tions with multiresistant bacteria in the EU and the
European Economic Area in 2015 [90]. The authors of
this study estimated based on a population-level model-
ing analysis that 671 689 infections with antibiotic-
resistant bacteria, of which 63.5% (426 277 of 671 689)
were associated with health care and estimated ~33 000
attributable deaths and over 800 000 disability-adjusted
life-years [90]. Furthermore the CDC listed in newest
report the worst superbugs into three categories urgent
threats,”“serious threatsand concerning threats
including a watch list(Table 3). Currently 21 different
superbugs are listed by CDC.
All these worst data about superbugs, incidence,
complications and mortality together showing in one
direction, that infection with antibiotic-resistant bacteria
are threatening modern health care worldwide. Overall,
both politically and health care providers need to
rethink innovative new ideas to fight against multi-
resistant bacteria. Due to the decrease in the number of
new antibiotics [2], additional procedures such as phage
therapy [91, 92], CAP [93, 94] or here the photody-
namic principle using photoantimicrobials need to be
given more attention now, otherwise Jim O'Neill's prog-
nosis will come true for deaths per year by AMR Germs
in the year 2050 [1].
TABLE 3 List of current Superbugs
Priority ranking
Bacteria and Fungi listed in
the AMR report 2019 [88]
Urgent threats Carbapenem-resistant
Acinetobacter
Candida auris
Clostridioides difficile
Carbapenem-resistant
Enterobacteriaceae
Drug-resistant Neisseria
gonorrhoeae
Serious threats Drug-resistant Campylobacter
Drug-resistant Candida
ESBL-producing
Enterobacteriaceae
Vancomycin-resistant
Enterococci (VRE)
Multidrug-resistant
Pseudomonas aeruginosa
Drug-resistant nontyphoidal
Salmonella
Drug-resistant Salmonella
serotype Typhi
Drug-resistant Shigella
Methicillin-resistant
Staphylococcus aureus
(MRSA)
Drug-resistant Streptococcus
pneumoniae
Drug-resistant Tuberculosis
Concerning threats Erythromycin-resistant Group
A Streptococcus
Clindamycin-resistant Group B
Streptococcus
Watch list Azole-resistant Aspergillus
fumigatus
Drug-resistant Mycoplasma
genitalium
Drug-resistant Bordetella
pertussis
6of9 MAISCH
8|OUTLOOKFUTURE
DEVELOPMENTS
Besides the development of new photoantimicrobials with
low molecular weight and/or amphiphilic chemical side
chains for better attachment/uptake by the bacteria, there
is a new trend in pharmacology to use so-called photo-
switchesto gain control over the effects of such bioactive
molecules by light [9598]. Here the activity of antimicro-
bial substances is controlled by light (light is switched on
or off for activation), because photo-responsive molecules
have been incorporated into the core structure of the anti-
microbial substance through chemical reactions [96].
Wegener et al. could demonstrate for the first time that
light of various wavelengths can control the antibacterial
activity of diaminopyrimidines bearing azobenzene photo-
switches [96]. This makes it possible to completely control
the activity of antibacterial agents after systemic adminis-
tration by triggering its activity through the effect of light
on the area of interest only. Such antimicrobial photo-
switches would then significantly reduce the possible side
effects of antibacterial substances after systemic adminis-
tration. Such photoswitches in fact, such antibacterial pho-
toswitches are suitable to control both activation and
deactivation of the antibacterial effect against bacteria,
especially where it is necessary to kill bad bacteria but to
preserve the commensal microflora and surrounding tissue
to achieve a therapeutic window.
ORCID
Tim Maisch https://orcid.org/0000-0002-1197-2628
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How to cite this article: Maisch T.
PhotoantimicrobialsAn update. Translational
Biophotonics. 2020;2:e201900033. https://doi.org/
10.1002/tbio.201900033
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