Photodynamic inhibition of Trichophyton rubrum: in vitro activity and the role of oxidative and nitrosative bursts in fungal death

Baltazar, Ludmila de Matos; Soares, Betânia Maria; Carneiro, Hellem Cristina Silva; Ávila, Thiago Vinicius; Gouveia, Ludmila Ferreira; Souza, Danielle G.; Ferreira, Marta Araújo Tavares; Pinotti, Marcos; Santos, Danielle Anjos dos; Cisalpino, Patrícia Silva

doi:10.1093/jac/dks414

Cited by 53 publications

(65 citation statements)

References 48 publications

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“…Pc 4-PDT also demonstrated an excellent safety profile in a phase 1 trial on cutaneous neoplasms (25). Although the susceptibility of T. rubrum to PDT using other photosensitizers has been extensively investigated in vitro, the mechanism of phototoxicity has not been clearly defined (2,9,(26)(27)(28). In this study, we showed that a common dose of Pc 4-PDT can induce cell death in microconidia (terbinafine-sensitive and -resistant strains of T. rubrum).…”

mentioning

confidence: 77%

Silicon Phthalocyanine 4 Phototoxicity in Trichophyton rubrum

Lam

Dimaano

Oyetakin-White

et al. 2014

Antimicrob Agents Chemother

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dTrichophyton rubrum is the leading pathogen that causes long-lasting skin and nail dermatophyte infections. Currently, topical treatment consists of terbinafine for the skin and ciclopirox for the nails, whereas systemic agents, such as oral terbinafine and itraconazole, are also prescribed. These systemic drugs have severe side effects, including liver toxicity. Topical therapies, however, are sometimes ineffective. This led us to investigate alternative treatment options, such as photodynamic therapy (PDT). Although PDT is traditionally recognized as a therapeutic option for treating a wide range of medical conditions, including agerelated macular degeneration and malignant cancers, its antimicrobial properties have also received considerable attention. However, the mechanism(s) underlying the susceptibility of dermatophytic fungi to PDT is relatively unknown. As a noninvasive treatment, PDT uses a photosensitizing drug and light, which, in the presence of oxygen, results in cellular destruction. In this study, we investigated the mechanism of cytotoxicity of PDT in vitro using the silicon phthalocyanine (Pc) 4 [SiPc(OSi(CH 3 ) 2 (CH 2 ) 3 N(CH 3 ) 2 )(OH)] in T. rubrum. Confocal microscopy revealed that Pc 4 binds to cytoplasmic organelles, and upon irradiation, reactive oxygen species (ROS) are generated. The impairment of fungal metabolic activities as measured by an XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) assay indicated that 1.0 M Pc 4 followed by 670 to 675 nm light at 2.0 J/cm 2 reduced the overall cell survival rate, which was substantiated by a dry weight assay. In addition, we found that this therapeutic approach is effective against terbinafine-sensitive (24602) and terbinafine-resistant (MRL666) strains. These data suggest that Pc 4-PDT may have utility as a treatment for dermatophytosis. Utilizing mainly keratin for their source of energy, dermatophytes can cause dermatophytosis or tinea of the skin, hair, and nails that impact the quality of life of infected patients, especially in immunocompromised individuals. Trichophyton rubrum is the main culprit of superficial mycosis of the nail (onychomycosis), which is often long lasting and has a high incidence of recurrence. Onychomycosis affects 10% of the general population, 20% of the population older than 60 years, 50% of people older than 70 years, and 30% of diabetic patients, and it can often result in pain, disability, and psychosocial stress, therefore significantly reducing quality of life (1-3). The conventional treatments involve excruciating surgical nail avulsion and toxic systemic antifungal drugs. Topical therapy is a less invasive and hence more attractive treatment for the eradication of fungal infection. However, dismal patient compliance often contributes to the high rate of unsuccessful treatment (4). It is for these reasons that alternative therapeutic agents need to be developed that can effectively target T. rubrum without significantly harming the host.In vitro studies have dem...

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confidence: 77%

Silicon Phthalocyanine 4 Phototoxicity in Trichophyton rubrum

Lam

Dimaano

Oyetakin-White

et al. 2014

Antimicrob Agents Chemother

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“…The fungal cells were grown in YPD medium for 7 days at 35 to 37°C in the presence or absence of L-DOPA and suspended in PBS to achieve 1 ϫ 10 7 viable cells/ml. The final concentrations of inocula for susceptibility tests and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays were 0.5 ϫ 10 5 to 1 ϫ 10 5 yeast cells/ml for the antifungal tests and 1 ϫ 10 6 cells/ml for the aPI tests (19,24).…”

Section: Fungal Isolatesmentioning

confidence: 99%

“…Toluidine blue (TBO) (Sigma, St. Louis, MO, USA) was used as a photosensitizer at concentrations of 70 mg/liter, 40 mg/liter, and 10 mg/liter. A light-emitting diode (LED) (Fisioled; MMoptics, São Paulo, Brazil) was used as a source of monochromatic light (19). The energy doses tested were 30 J/cm 2 , 60 J/cm 2 , and 90 J/cm 2 .…”

Section: Fungal Isolatesmentioning

confidence: 99%

“…In the type I reaction, after the transfer of an electron from the PS to biological molecules, the production of different reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as superoxide anion, hydrogen peroxide, and peroxynitrite (ONOO ⅐ ), occurs. In the type II reaction, there is transfer of energy from the PS to molecular oxygen, forming an oxygen singlet, which is the main mediator of cell injury after aPI (17)(18)(19)(20).…”

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confidence: 99%

“…The effectiveness of photodynamic inhibition as a fungicidal and bactericidal agent has been demonstrated by different authors (17,19,(21)(22)(23), although little is known about aPI, its mechanism of action against dimorphic fungi, and the influence of melanin on the effects of aPI. Considering that melanin has antioxidant properties, the aim of this study was to evaluate the effects of aPI and of classical antifungal drugs in nonmelanized and melanized Paracoccidioides sp.…”

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confidence: 99%

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Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

Baltazar

Werneck

Soares

et al. 2015

Antimicrob Agents Chemother

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c Paracoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced by Paracoccidioides spp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production by Paracoccidioides yeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI. P aracoccidioidomycosis (PCM) is a systemic disease endemic to Latin America and South America that can be fatal if not treated (1). In Brazil, PCM is a serious health problem and is the most important cause of death among the systemic mycoses in immunocompetent patients (1-3). The etiological agents of PCM, dimorphic fungi that present a filamentous form at 25°C and yeast forms at 37°C, belong to the Paracoccidioides species complex, which includes four known phylogenetic lineages, Pb01-like (or Paracoccidioides lutzii), S1, PS2, and PS3 (Paracoccidioides brasiliensis) (4-7). Thermal dimorphism is a survival strategy to resist the host environment (5, 7). It includes secretion of proteases and melanin synthesis as putative virulence factors contributing to the protection of yeast cells from environmental stressors (8).Currently, there has been much discussion about the role of melanin as a putative virulence factor of several fungal species, such as Histoplasma capsulatum, Sporothrix schenckii, and Cryptococcus neoformans (8-11). Melanin is a multifunctional polymer synthesized from 1,8-dihydroxynaphthalene (DHN) by the pentakide pathway or formed when cells grow in the presence of phenolic compounds, such as L-3,4-dihydroxyphenylalanine (L-DOPA) (12). Typically, it is a brown to black pigment formed through the activity of the phenoloxidase enzyme (laccase) on phenolic compounds (8, 13). Its influence on the biology of fungal cells is better ...

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Light treatments of nail fungal infections

Houang

Perrone

Mawad

et al. 2018

Journal of Biophotonics

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Nail fungal infections are notoriously persistent and difficult to treat which can lead to severe health impacts, particularly in the immunocompromized. Current antifungal treatments, including systemic and topical drugs, are prolonged and do not effectively provide a complete cure. Severe side effects are also associated with systemic antifungals, such as hepatotoxicity. Light treatments of onychomycosis are an emerging therapy that has localized photodynamic, photothermal or photoablative action. These treatments have shown to be an effective alternative to traditional antifungal remedies with comparable or better cure rates achieved in shorter times and without systemic side effects. This report reviews significant clinical and experimental studies in the field, highlighting mechanisms of action and major effects related to light therapy; in particular, the impact of light on fungal genetics.

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Photodynamic inhibition of Trichophyton rubrum: in vitro activity and the role of oxidative and nitrosative bursts in fungal death

Cited by 53 publications

References 48 publications

Silicon Phthalocyanine 4 Phototoxicity in Trichophyton rubrum

Silicon Phthalocyanine 4 Phototoxicity in Trichophyton rubrum

Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

Light treatments of nail fungal infections

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