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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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PhotoantimicrobialsAn update
Tim Maisch
Department of Dermatology, University
Medical Center Regensburg, Regensburg,
Tim Maisch, Department of Dermatology,
University Medical Center Regensburg,
Franz-Josef-Strauß-Allee 11, 93053
Regensburg, Germany.
Email: tim.maisch@klinik.uni-
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.
light-activated antimicrobial surface, photoantimicrobials, photodynamic, potentiation
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. 1of9
(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
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%
Curcumin SACUR Positive charges, core-molecule
curumin approved as E100 food additive
Phenalenones SAPYR Positive charge, singlet oxygen quantum
yield of ~99%, low molecular weight,
substantial effects on bacterial biofilms
Triphenylphosphonium TPP Selective killing of Gram-positive bacteria
in presence of Gram-negative
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
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].
3.1 |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
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
) 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].
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].
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].
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].)
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
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
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].
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].
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
Candida auris
Clostridioides difficile
Drug-resistant Neisseria
Serious threats Drug-resistant Campylobacter
Drug-resistant Candida
Enterococci (VRE)
Pseudomonas aeruginosa
Drug-resistant nontyphoidal
Drug-resistant Salmonella
serotype Typhi
Drug-resistant Shigella
Staphylococcus aureus
Drug-resistant Streptococcus
Drug-resistant Tuberculosis
Concerning threats Erythromycin-resistant Group
A Streptococcus
Clindamycin-resistant Group B
Watch list Azole-resistant Aspergillus
Drug-resistant Mycoplasma
Drug-resistant Bordetella
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.
Tim Maisch
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How to cite this article: Maisch T.
PhotoantimicrobialsAn update. Translational
Biophotonics. 2020;2:e201900033.
... The photobiological effect of the extract was evaluated against cells of different cancer cell lines, cells of a non-malignant cell line, and grampositive bacteria (i.e., Staphylococcus aureus). The latter selection was made to test additionally the potential of the extract, and its fungal photosensitizers, as agents for the photodynamic therapy (PDT) [15,16] and photodynamic inactivation (PDI, also called photoantimicrobial chemotherapy (PACT) [17,18]). Both therapy forms are based on effects induced by the synergistic action of a light-absorbing molecule, the so-called photosensitizer (PS), and light. ...
... Consequently, a selective mode of action can be envisioned, turning these therapy forms into highly promising alternatives. PDI or PACT is treated as one alternative to combat the antimicrobial resistance crisis [17], as PSs showed activity against resistant microorganisms and themselves did not induce resistance. With the increasing portfolio of delicate irradiation devices [19], PDT is an especially appealing treatment option for non-operatable tumors of the head and neck or prostate [20]. ...
The colorful agaricoid fruiting bodies of dermocyboid Cortinarii owe their magnificent hue to a mixture of anthraquinone (AQ) pigments. Recently, it was discovered that some of these fungal anthraquinones have an impressive photopharmacological effect. The question, therefore, arises as to whether these pigments are also of ecological or functional significance. According to the optimal defense hypothesis, toxic molecules should be enriched in spore-producing structures, such as the gills of agarics. To test this hypothesis, we studied the distribution of fungal AQs in the fruiting body of Cortinarius rubrophyllus. The fungus belongs to the well-studied Cortinarius subgenus Dermocybe but has not been chemically characterized. Here, we report on the pigment profile of this beautiful fungus and focus on the distribution of anthraquinone pigments in the fruiting body for the first time. Here it is statistically confirmed that the potent photosensitizer emodin is significantly enriched in the gills. Furthermore, we show that the extract is photoactive against cancer cells and bacteria.
... Delivery of the PS has been accomplished through the use of several carriers. 7,9,10 Proteins appear as useful carriers due to their intrinsic biocompatibility. We have previously reported water-soluble proteins as delivery systems for antimicrobial PDI, exploiting their non-covalent binding capability toward hydrophobic PS molecules. ...
Full-text available
We report the development of a supramolecular structure endowed with photosensitizing properties and targeting capability for antimicrobial photodynamic inactivation. Our synthetic strategy uses the tetrameric bacterial protein streptavidin, labeled with the photosensitizer eosin, as the main building block. Biotinylated immunoglobulin G (IgG) from human serum, known to associate with Staphylococcus aureus protein A, was bound to the complex streptavidin-eosin. Fluorescence correlation spectroscopy and fluorescence microscopy demonstrate binding of the complex to S. aureus. Efficient photoinactivation is observed for S. aureus suspensions treated with IgG-streptavidin-eosin at concentrations higher than 0.5 μM and exposed to green light. The proposed strategy offers a flexible platform for targeting a variety of molecules and microbial species.
... Riboflavin, vitamin B2, is a well-known flavin that is present in a broad range of organisms, such as human tissues, plant leaves, mushrooms, and eggs [24]. Riboflavin, which has two absorption peaks in the UVA (360 nm) and blue (visible, 440 nm) regions, has been used in APDT [23,101]. It also has a high quantum yield and substantially inhibits the growth of antibiotic-resistant bacteria such as enterohemorrhagic E. coli and MRSA [24]. ...
Full-text available
Health problems and reduced treatment effectiveness due to antimicrobial resistance have become important global problems and are important factors that negatively affect life expectancy. Antimicrobial photodynamic therapy (APDT) is constantly evolving and can minimize this antimicrobial resistance problem. Reactive oxygen species produced when nontoxic photosensitizers are exposed to light are the main functional components of APDT responsible for microbial destruction; therefore, APDT has a broad spectrum of target pathogens, such as bacteria, fungi, and viruses. Various photosensitizers, including natural extracts, compounds, and their synthetic derivatives, are being investigated. The main limitations, such as weak antimicrobial activity against Gram-negative bacteria, solubility, specificity, and cost, encourage the exploration of new photosensitizer candidates. Many additional methods, such as cell surface engineering, cotreatment with membrane-damaging agents, nanotechnology, computational simulation, and sonodynamic therapy, are also being investigated to develop novel APDT methods with improved properties. In this review, we summarize APDT research, focusing on natural photosensitizers used in in vitro and in vivo experimental models. In addition, we describe the limitations observed for natural photosensitizers and the methods developed to counter those limitations with emerging technologies.
Alternative therapies against pathogens are under intense investigation because of their increasing resistance to antibiotics. Photodynamic therapy (PDT) is one such alternative that has shown promising results. However, for the widespread use of PDT, it is essential to decipher underlying mechanisms, so as to improve PDT’s therapeutic applications. Because of this, we have studied biochemical changes in pathogen Pseudomonas aeruginosa, a medically important bacteria that has developed antibiotic resistance, after PDT with curcumin photosensitizer. Results show a drastic decrease in α-helix protein and increased disordered and β-sheet secondary structure proteins in P. Aeruginosa post-PDT compared to control. Interestingly, these biochemical changes differ from PDT of pathogens Leishmania braziliensis and Leishmania major with photosensitizer methylene blue. This observation underlines the need for extensive studies on PDT of different pathogens to understand mechanisms of action and develop better PDT strategies.
Photodynamic therapy (PDT) is a clinically approved procedure that can exert a curative action against malignant cells. The treatment implies the administration of a photoactive molecular species that, upon absorption of visible or near infrared light, sensitizes the formation of reactive oxygen species. These species are cytotoxic and lead to tumor cell death, damage vasculature, and induce inflammation. Clinical investigations demonstrated that PDT is curative and does not compromise other treatment options. One of the major limitations of the original method was the low selectivity of the photoactive compounds for malignant over healthy tissues. The development of conjugates with antibodies has endowed photosensitizing molecules with targeting capability, so that the compounds are delivered with unprecedented precision to the site of action. Given their fluorescence emission capability, these supramolecular species are intrinsically theranostic agents.
The current viral pandemic has highlighted the compelling need for effective and versatile treatments, that can be quickly tuned to tackle new threats, and are robust against mutations. Development of such treatments is made even more urgent in view of the decreasing effectiveness of current antibiotics, that makes microbial infections the next emerging global threat. Photodynamic effect is one such method. It relies on physical processes proceeding from excited states of particular organic molecules, called photosensitizers, generated upon absorption of visible or near infrared light. The excited states of these molecules, tailored to undergo efficient intersystem crossing, interact with molecular oxygen and generate short lived reactive oxygen species (ROS), mostly singlet oxygen. These species are highly cytotoxic through non-specific oxidation reactions and constitute the basis of the treatment. In spite of the apparent simplicity of the principle, the method still has to face important challenges. For instance, the short lifetime of ROS means that the photosensitizer must reach the target within a few tens nanometers, which requires proper molecular engineering at the nanoscale level. Photoactive nanostructures thus engineered should ideally comprise a functionality that turns the system into a theranostic means, for instance, through introduction of fluorophores suitable for nanoscopy. We discuss the principles of the method and the current molecular strategies that have been and still are being explored in antimicrobial and antiviral photodynamic treatment.
Full-text available
Antimicrobial photodynamic inactivation (aPDI) and antimicrobial blue light (aBL) are considered low-risk treatments for the development of bacterial resistance and/or tolerance due to their multitargeted modes of action. In this study, we assessed the development of Staphylococcus aureus tolerance to these phototreatments. Reference S. aureus USA300 JE2 was subjected to 15 cycles of both sub-lethal aPDI (employing an exogenously administered photosensitizer (PS), i.e., rose Bengal (RB)) and sub-lethal aBL (employing endogenously produced photosensitizing compounds, i.e., porphyrins). We demonstrate substantial aPDI/aBL tolerance development and tolerance stability after 5 cycles of subculturing without aPDI/aBL exposure (the development of aPDI/aBL tolerance was also confirmed with the employment of clinical MRSA and MSSA strain as well as other representatives of Gram-positive microbes, i.e. Enterococcus faecium and Streptococcus agalactiae). In addition, a rifampicin-resistant (RIFR) mutant selection assay showed an increased mutation rate in S. aureus upon sub-lethal phototreatments, indicating that the increased aPDI/aBL tolerance may result from accumulated mutations. Moreover, qRT-PCR analysis following sub-lethal phototreatments demonstrated increased expression of umuC, which encodes stress-responsive error-prone DNA polymerase V, an enzyme that increases the rate of mutation. Employment of recA and umuC transposon S. aureus mutants confirmed SOS-induction dependence of the tolerance development. Interestingly, aPDI/aBL-tolerant S. aureus exhibited increased susceptibility to gentamicin (GEN) and doxycycline (DOX), supporting the hypothesis of genetic alterations induced by sub-lethal phototreatments. The obtained results indicate that S. aureus may develop stable tolerance to studied phototreatments upon sub-lethal aPDI/aBL exposure; thus, the risk of tolerance development should be considered significant when designing aPDI/aBL protocols for infection treatments in vitro and in clinical settings.
Full-text available
The emergence of antimicrobial drug resistance requires development of alternative therapeutic options. Multidrug-resistant strains of Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter spp. are still the most commonly identified antimicrobial-resistant pathogens. These microorganisms are part of the so-called 'ESKAPE' pathogens to emphasize that they currently cause the majority of hospital acquired infections and effectively 'escape' the effects of antibacterial drugs. Thus, alternative, safer and more efficient antimicrobial strategies are urgently needed, especially against 'ESKAPE' superbugs. Antimicrobial photodynamic inactivation is a therapeutic option used in the treatment of infectious diseases. It is based on a combination of a photosensitizer, light and oxygen to remove highly metabolically active cells.
Full-text available
Nosocomial infections are a major threat to modern therapeutics. The major causative agent of these infections is multidrug-resistant gram-negative bacteria, which impart high morbidity and mortality rate. This has led to an urge for the development of new antibiotics. Antimicrobial photodynamic therapy is a promising strategy to which till date no resistant strain has been reported. Since the efficacy of photodynamic therapy largely depends on the selection and administration of an appropriate photosensitizer, therefore, the realization of clinically active photosensitizers is an immediate need. Here, by using E. coli as a study model we have demonstrated the antimicrobial photodynamic potential of riboflavin. Intracellular ROS formation by DCFH-DA assay, lipid peroxidation, protein carbonylation, LDH activity was measured in treated bacterial samples. Enzymatic (SOD, CAT, GSH) antioxidants and non-enzymatic (GSH) was further evaluated. Bacterial death was confirmed by colony forming assay, optical microscopy and scanning electron microscopy. The treated bacterial cells exhibited abundant ROS generation and marked increment in the level of oxidative stress markers as well as significant reduction in LDH activity. Marked reduction in colony forming units was also observed. Optical microscopic and SEM images further confirmed the bacterial death. Thus, we can say that photoilluminated riboflavin renders the redox status of bacterial cells into a compromised state leading to significant membrane damage ultimately causing bacterial death. This study aims to add one more therapeutic dimension to photoilluminated riboflavin as it can be effectively employed in targeting bacterial biofilms occurring on hospital wares causing several serious medical conditions.
Full-text available
During antimicrobial photodynamic inactivation (APDI) in the treatment of an infection, it is likely that microorganisms would be exposed to sub-lethal doses of APDI (sAPDI). Although sAPDI cannot kill microorganisms, it can significantly affect microbial virulence. In this study, we evaluated the effect of sAPDI using methylene blue (MB) on the expression of genes belonging to two quorum sensing (QS) operons (rhl and las systems) and two genes necessary for biofilm formation (pelF and pslA) under QS control in Pseudomonas aeruginosa. Biofilm formation ability of P. aeruginosa ATCC 27853 exposed to sAPDI (MB at 0.012 mM and light dose of 23 J/cm²) was evaluated using triphenyl tetrazolium chloride (TTC) assay and scanning electron microscopy (SEM). The effect of sAPDI on expression of rhlI, rhlR, lasI, lasR, pelF, and pslA were also evaluated by quantitative real-time polymerase chain reaction. Quantitative assay (TTC) results and morphological observations (SEM) indicated that a single sAPDI treatment resulted in a significant decrease in biofilm formation ability of P. aeruginosa ATCC 27853 compared to their non-treated controls (P = 0.012). These results were consistent with the expression of genes belonging to rhl and las systems and pelF and pslA genes. The results suggested that the transcriptional decreases caused by MB-sAPDI did lead to phenotypic changes.
Increasingly, clinical infections are becoming recalcitrant or completely resistant to antibiotics treatment and multidrug resistance is rising alarmingly. Patients suffering from infections that used to be treated successfully by antibiotic regimens are running out of the treatment options. Bacteriophage (phage) therapy, long practiced in parts of Eastern Europe and the states of the former Soviet Union, is now being reevaluated as a treatment option complementary to and synergistic with antibiotic treatments. We discuss some current studies that have addressed synergistic killing activity between phages and antibiotics, the issues of treatment order and antibiotic class, and point to considerations that will have to be addressed by future studies. Overall, co-treatments with phages and antibiotics promise to extend the utility of antibiotics in current use. Nevertheless, a lot of work, both basic and clinical, remains to be done before such co-treatments become routine options in the hospital setting.
Photodynamic Inactivation based on either sodium magnesium chlorophyllin combined with chelators or the novel chlorin e6 derivative B17-0024 is effective in photokilling Gram+ and Gram− bacterial phytopathogens.
Burgeoning problems of antimicrobial resistance dictate that new solutions be developed to combat old foes. Use of lytic bacteriophages (phages) for the treatment of drug-resistant bacterial infections is one approach that has gained significant traction in recent years. Fueled by reports of experimental phage therapy cases with very positive patient outcomes, several early-stage clinical trials of therapeutic phage products have been launched in the United States. Eventual licensure enabling widespread access to phages is the goal; however, new paths to regulatory approval and mass-market distribution, distinct from those of small-molecule antibiotics, must be forged first. This review highlights unique aspects related to the clinical use of phages, including advantages to be reaped as well as challenges to be overcome. Expected final online publication date for the Annual Review of Microbiology Volume 73 is September 9, 2019. Please see for revised estimates.
Herein, a novel nano-system IF7-ROSPCNP, which is O 2 -evolving and reactive oxygen species (ROS)-activable, was developed for enhancing the combination chemotherapy and photodynamic therapy (PDT). The nanoparticles composed of photosensitizers (disulfonated meso-tetraphenylporphine, TPPS2a) and catalase in the inner core, doxorubicin (DOX) in the polymeric shell and functionalized on its surface with IF7 peptide, which specially bind to annexin 1. As confirmed that the structure of IF7-ROSPCNP was able to remain intact under normal physiological conditions. After IF7-ROSPCNP was selectively entrapped by the annexin 1-positive and ROS-abundant MCF-7/ADR cells, the shell of nanoparticles was ruptured and the entrapped photosensitizers were completely released out. Under irradiation, ROS was continuously produced and the DOX, which was conjugated to the terminal of polylactic copolymer (mPEG-PLA) by a ROS-cleavable linkage, was subsequently released. With such strategy, cellular uptake of drugs was dramatically improved resulted in an enhanced cytotoxicity and anti-tumor effect on drug resistant cancer.
Background: Antimicrobial photodynamic therapy (aPDT) is a growing approach to treat skin and mucosal infections. Despite its effectiveness, investigators have explored whether aPDT can be further combined with antibiotics and antifungal drugs. Objective: To systematically assess the in vivo studies on the effectiveness of combinations of aPTD plus antimicrobials in the treatment of cutaneous and mucosal infections. Materials and methods: Searches were performed in four databases (PubMed, EMBASE, Cochrane library databases, until July 2018. The pooled information was evaluated according to the PRISMA guidelines. Results: 11 full-text articles were finally evaluated and included. The best aPDT combinations involved 5-aminolevulinic acid or phenothiazinium dye-based aPDT. In general, the combination shows benefits such as reducing treatment times, lowering drug dosages, decreasing drug toxicity, improving patient compliance and diminishing the risk of developing resistance. The mechanism of action may be that first aPDT damages the microbial cell wall or membrane, which allows better penetration of the antimicrobial drug. Limitations: The number of studies was low, the protocols used were heterogeneous, and there was a lack of clinical trials. Conclusions: The additive or synergistic effect of aPDT combined with antimicrobials could be promising to manage skin and mucosal infections, helping to overcome the microbial drug resistance.
Point prevalence surveys of healthcare-associated infections (HAI) and antimicrobial use in the European Union and European Economic Area (EU/EEA) from 2016 to 2017 included 310,755 patients from 1,209 acute care hospitals in 28 countries. After national validation, we estimated that 6.5% (cumulative 95% confidence interval (cCI): 5.4–7.8%) patients in acute care hospitals had at least one HAI (country-weighted prevalence). On any given day, 98,166 patients (95% cCI: 81,022–117,484) in acute care hospitals had an HAI; 3.8 million (95% cCI: 3.1–4.5 million) patients acquired an HAI each year. Our study confirmed a high annual number of HAI in healthcare facilities in the EU/EEA.