Induction of ROS generation by fluconazole in Candida glabrata: activation of antioxidant enzymes and oxidative DNA damage

Mahl, Camila D.; Behling, Camile S.; Hackenhaar, Fernanda Schäfer; Silva, Mélany Natuane de Carvalho e; Putti, Jordana Salete; Salomon, Tiago Boeira; Alves, Sydney Hartz; Fuentefría, Alexandre Meneghello; Benfato, Mara da Silveira

doi:10.1016/j.diagmicrobio.2015.03.019

Cited by 48 publications

(40 citation statements)

References 33 publications

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“…C. parapsilosis ATCC22019 was the least resistant species [ 47 ], with 2 mg/L (2.38% of the maximum dose), followed by C. albicans SC5314, with 3 mg/L (3.57% of the maximum dose) ( Table 2 ). The MBEC values obtained were higher than previously reported for other C. albicans strains [ 84 , 85 , 86 ], but were similar for C. parapsilosis [ 87 , 88 ]. The differences observed could be due to alterations in the biofilm formation conditions, and the fact that the MBEC evaluations methods used were not identical.…”

Section: Resultscontrasting

confidence: 52%

Liposomal and Deoxycholate Amphotericin B Formulations: Effectiveness against Biofilm Infections of Candida spp.

Rodrigues

Henriques

2017

Pathogens

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Background: candidiasis is the primary fungal infection encountered in patients undergoing prolonged hospitalization, and the fourth leading cause of nosocomial bloodstream infections. One of the most important Candida spp. virulence factors is the ability to form biofilms, which are extremely refractory to antimicrobial therapy and very difficult to treat with the traditional antifungal therapies. It is known that the prophylaxis or treatment of a systemic candidiasis are recurrently taken without considering the possibility of a Candida spp. biofilm-related infections. Therefore, it is important to assess the effectiveness of the available drugs and which formulations have the best performance in these specific infections. Methods: 24-h-biofilms of four Candida spp. and their response to two amphotericin B (AmB) pharmaceutical formulations (liposomal and deoxycholate) were evaluated. Results: generally, Candida glabrata was the less susceptible yeast species to both AmBs. MBECs revealed that it is therapeutically more appealing to use AmB-L than AmB-Deox for all Candida spp. biofilms, since none of the determined concentrations of AmB-L reached 10% of the maximum daily dose, but both formulations showed a very good capacity in the biomass reduction. Conclusions: the liposomal formulation presents better performance in the eradication of the biofilm cells for all the species in comparison with the deoxycholate formulation.

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Section: Resultscontrasting

confidence: 52%

Liposomal and Deoxycholate Amphotericin B Formulations: Effectiveness against Biofilm Infections of Candida spp.

Rodrigues

Henriques

2017

Pathogens

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“…Increasing evidence demonstrated that oxidative damage induced by endogenous ROS was involved in the antifungal activity of antifungal agents [7][8][9][10][11][12]24 . Kobayashi et al reported that the ROS production of C. albicans were significantly increased in a dose-dependent manner after treated with 0.125 (MIC), 1.25, and 12.5 μg/ mL miconazole, respectively.…”

Section: Discussionmentioning

confidence: 99%

A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

Cao

et al. 2020

Sci Rep

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In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, BN-3b with antifungal activity against Candida albicans, was achieved. In this study, we found that oxidative damage induced by endogenous reactive oxygen species (ROS) plays an important role in the antifungal activity of BN-3b. Further investigation indicated that BN-3b stimulated ROS accumulation, increased malondialdehyde (MDA) levels, and decreased reduced/oxidized glutathione (GSH/GSSG) ratio. Moreover, BN-3b decreased mitochondrial membrane potential (MMP) and ATP generation. Ultrastructure analysis revealed that BN-3b severely damaged the cell membrane of C. albicans. Quantitative PCR (RT-qPCR) analysis revealed that virulence factors of C. albicans SAPs, PLB1, PLB2, HWP1, ALSs, and LIPs were all down-regulated after BN-3b exposure. We also found that BN-3b markedly inhibited the hyphal formation of C. albicans. In addition, in vivo studies revealed that BN-3b significantly prolonged survival and decreased fungal burden in mouse model of disseminated candidiasis.Candida albicans is an opportunistic fungal pathogen 1 , causing skin and mucosal infections in healthy individuals 2 . Moreover, C. albicans can cause fatal systemic disease when immune function is damaged 3 . Disseminated candidiasis caused by C. albicans is the main cause of death in immunocompromised patients 3,4 .Borrelidin (BN), an 18-membered macrolide polyketide 5 , was isolated from the fermentation broth of Streptomyces vinaceusdrappus 6 . In the process of investigating the antifungal SAR of BN and discovering antifungal leads, forty-seven borrelidin derivatives (BNs) were synthesized by our research group 5 . Among them, a BN ester analogue BN-3b was greatly promising antifungal candidate. The MIC (minimum inhibitory concentration) values of BN-3b against C. albicans and Candida parapsilosis were 50 μg/mL and 12.5 μg/mL, respectively (Table 1). In this study, we will explore the antifungal mechanism of BN-3b.Several studies have suggested that endogenous ROS mediated oxidative damage participate in the antifungal activity of amphotericin B (AMB) and fluconazole (FLC) 7-11 . These findings implied that oxidative stress involved in the antifungal mechanism of antifungal agents. ROS are the byproducts of cellular metabolism and mainly produced in the mitochondria 12 . However, overproduction of ROS resulted in damage of nucleic acids, proteins, and lipids 4 .C. albicans has developed an effective battery of virulence factors 13 that promote disease establishment and progression 14 . Among these virulence factors, lipases (LIPs), phospholipases, agglutinin-like sequences (ALSs), secreted aspartyl proteinases (SAPs), and hyphal wall protein (HWP1) are most significant in virulence [14][15][16][17] . Fungal virulence factors are potential targets for drug development 15 . In this study, we determined the expression of virulence factors (SAPs, PLB1, PLB2, HWP1, ALSs, and LIP...

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“…ROS generation leading to oxidative damage is well known for the cause of DNA damage [ 26 ]. Moreover, enhanced ROS generation as demonstrated from this study in both the pathogens necessitated exploring the DNA damage in response to MB.…”

Section: Resultsmentioning

confidence: 99%

Nonphotodynamic Roles of Methylene Blue: Display of Distinct Antimycobacterial and Anticandidal Mode of Actions

Pal

Ansari

Saibabu

et al. 2018

Journal of Pathogens

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Significance of methylene blue (MB) in photodynamic therapy against microbes is well established. Previously, we have reported the antifungal potential of MB against Candida albicans. The present study attempts to identify additional antimicrobial effect of MB against another prevalent human pathogen, Mycobacterium tuberculosis (MTB). We explored that MB is efficiently inhibiting the growth of Mycobacterium at 15.62 μg/ml albeit in bacteriostatic manner similar to its fungistatic nature. We uncovered additional cell surface phenotypes (colony morphology and cell sedimentation rate) which were impaired only in Mycobacterium. Mechanistic insights revealed that MB causes energy dependent membrane perturbation in both C. albicans and Mycobacterium. We also confirmed that MB leads to enhanced reactive oxygen species generation in both organisms that could be reversed upon antioxidant supplementation; however, DNA damage could only be observed in Mycobacterium. We provided evidence that although biofilm formation was disrupted in both organisms, cell adherence to human epithelial cells was inhibited only in Mycobacterium. Lastly, RT-PCR results showed good correlation with the biochemical assay. Together, apart from the well-established role of MB in photodynamic therapy, this study provides insights into the distinct antimicrobial mode of actions in two significant human pathogens, Candida and Mycobacterium, which can be extrapolated to improve our understanding of finding novel therapeutic options.

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Induction of ROS generation by fluconazole in Candida glabrata: activation of antioxidant enzymes and oxidative DNA damage

Cited by 48 publications

References 33 publications

Liposomal and Deoxycholate Amphotericin B Formulations: Effectiveness against Biofilm Infections of Candida spp.

Liposomal and Deoxycholate Amphotericin B Formulations: Effectiveness against Biofilm Infections of Candida spp.

A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

Nonphotodynamic Roles of Methylene Blue: Display of Distinct Antimycobacterial and Anticandidal Mode of Actions

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