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Review
. 2021 Dec;12(1):2247-2272.
doi: 10.1080/21505594.2021.1960105.

Antimicrobial photodynamic therapy (aPDT) for biofilm treatments. Possible synergy between aPDT and pulsed electric fields

Wanessa de Cassia Martins Antunes de Melo  1 , Raimonda Celiešiūtė-Germanienė  1 , Povilas Šimonis  1 , Arūnas Stirkė  1
Affiliations
Review

Antimicrobial photodynamic therapy (aPDT) for biofilm treatments. Possible synergy between aPDT and pulsed electric fields

Wanessa de Cassia Martins Antunes de Melo et al. Virulence. 2021 Dec.

Abstract

Currently, microbial biofilms have been the cause of a wide variety of infections in the human body, reaching 80% of all bacterial and fungal infections. The biofilms present specific properties that increase the resistance to antimicrobial treatments. Thus, the development of new approaches is urgent, and antimicrobial photodynamic therapy (aPDT) has been shown as a promising candidate. aPDT involves a synergic association of a photosensitizer (PS), molecular oxygen and visible light, producing highly reactive oxygen species (ROS) that cause the oxidation of several cellular components. This therapy attacks many components of the biofilm, including proteins, lipids, and nucleic acids present within the biofilm matrix; causing inhibition even in the cells that are inside the extracellular polymeric substance (EPS). Recent advances in designing new PSs to increase the production of ROS and the combination of aPDT with other therapies, especially pulsed electric fields (PEF), have contributed to enhanced biofilm inhibition. The PEF has proven to have antimicrobial effect once it is known that extensive chemical reactions occur when electric fields are applied. This type of treatment kills microorganisms not only due to membrane rupture but also due to the formation of reactive compounds including free oxygen, hydrogen, hydroxyl and hydroperoxyl radicals. So, this review aims to show the progress of aPDT and PEF against the biofilms, suggesting that the association of both methods can potentiate their effects and overcome biofilm infections.

Keywords: Antimicrobial resistance1; EPS3; PEF6; ROS4; aPDT5; biofilms2; photosensitizer7 and electroporation8.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1.
Figure 1.
Adapted from [36]: Biofilm formation stages: 1) Reversible adhesion occurs when the planktonic cells adhere to a surface area (biotic or non-biotic) through the presence of a few virulence factors (adhesins, pili, flagellum, fimbriae, and glycocalyx) and chemical reactions (van der Waals forces, electrostatic forces, hydrophobic effects), starting the biofilm formation. At this stage, the microbial cells are susceptible to antimicrobials drugs. 2) Irreversible adhesion, at this step microorganisms start to grow and replicate, forming colonies that undergo transcriptional modifications for adherence, promoting an exchange of substrate, distribution of important metabolic products, and excretion of metabolic end-products; as well as secrete EPS making the biofilm cells less susceptible to host defense and antimicrobial drugs. 3) Biofilm maturation, at this phase the amount of ECM increases around the microcolonies due to continued secretion of EPS and beginning the intracellular communication system through the quorum-sensing molecules (QS), both are important factors of resistance. 4) Mature biofilm contains a high concentration of EPS and cavities between it that serve as transport channels of water, nutrients and planktonic cells throughout the biofilm community. 5) Biofilm dispersal involves the biofilms detachment due to the restriction of nutrients for the cells. This fact can occur by erosion and sloughing, and the cells search for another surface area to continue surviving.*EPS: extracellular polymeric substrate
Figure 2.
Figure 2.
Adapted from [59]: Polymicrobial biofilm interactions. Multiple-species biofilm can be found between the same species of microorganisms (neutral relationship) and between two or more species of microbes such as bacteria and fungi (antagonistic and synergistic relationship). Microbial antagonism produces toxic exoproducts and surface blanketing, while microbial synergy promotes antimicrobial resistance and cross-feeding
Figure 3.
Figure 3.
Adapted from [97]: ROS presents (a) a wide therapeutic window that affects different species of microorganisms (bacteria, fungi, virus and parasites) and (b) it is a nonselective multiple _target oxidizing various biomolecules, promoting substantial cell damage
Figure 4.
Figure 4.
Adapted from [10]: Jablonski diagram showing the photochemical and photophysical mechanism of aPDT
Figure 5.
Figure 5.
Adapted from [135]: Overview of photochemical reactions during aPDT represented by primary and secondary photochemistry reactions that produce ROS, promoting cytotoxic reaction that causes cellular damage
Figure 6.
Figure 6.
Hypothetical mechanism of action by the association of aPDT and PEF. a) Mature biofilm. b) Persister cells surrounded by EPS and the PS binding with the EPS and trying to reach the persister cells. c) Application of PEF, permeabilizing the PS diffusion through the EPS and cell membrane. d) Application of visible light, corresponding to the PS absorption. e) PS activation for ROS production. f) Production of ROS and its actions against both cells and EPS. e) The disruption of EPS, consequently also of the biofilm matrix and death of the microbial cell. PS returns to its ground state
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