Effect of Tetrandrine against Candida albicans Biofilms

PLOS ONE, Dec 2019

Candida albicans is the most common human fungal pathogen and has a high propensity to develop biofilms that are resistant to traditional antifungal agents. In this study, we investigated the effect of tetrandrine (TET) on growth, biofilm formation and yeast-to-hypha transition of C. albicans. We characterized the inhibitory effect of TET on hyphal growth and addressed its possible mechanism of action. Treatment of TET at a low concentration without affecting fungal growth inhibited hyphal growth in both liquid and solid Spider media. Real-time RT-PCR revealed that TET down-regulated the expression of hypha-specific genes ECE1, ALS3 and HWP1, and abrogated the induction of EFG1 and RAS1, regulators of hyphal growth. Addition of cAMP restored the normal phenotype of the SC5314 strain. These results indicate that TET may inhibit hyphal growth through the Ras1p-cAMP-PKA pathway. In vivo, at a range of concentrations from 4 mg/L to 32 mg/L, TET prolonged the survival of C. albicans-infected Caenorhabditis elegans significantly. This study provides useful information for the development of new strategies to reduce the incidence of C. albicans biofilm-associated infections.

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Effect of Tetrandrine against Candida albicans Biofilms

Citation: Zhao L-X, Li D-D, Hu D-D, Hu G-H, Yan L, et al. ( Effect of Tetrandrine against Candida albicans Biofilms Lan-Xue Zhao 0 De-Dong Li 0 Dan-Dan Hu 0 Gan-Hai Hu 0 Lan Yan 0 Yan Wang 0 Yuan-Ying Jiang 0 Tom Coenye, Ghent University, Belgium 0 1 New Drug Research and Development Center, School of Pharmacy, Second Military Medical University , Shanghai , China , 2 Department of Pharmacy, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine , Shanghai , China , 3 Department of Pharmacy, Fujian University of Traditional Chinese Medicine , Fuzhou , China Candida albicans is the most common human fungal pathogen and has a high propensity to develop biofilms that are resistant to traditional antifungal agents. In this study, we investigated the effect of tetrandrine (TET) on growth, biofilm formation and yeast-to-hypha transition of C. albicans. We characterized the inhibitory effect of TET on hyphal growth and addressed its possible mechanism of action. Treatment of TET at a low concentration without affecting fungal growth inhibited hyphal growth in both liquid and solid Spider media. Real-time RT-PCR revealed that TET down-regulated the expression of hypha-specific genes ECE1, ALS3 and HWP1, and abrogated the induction of EFG1 and RAS1, regulators of hyphal growth. Addition of cAMP restored the normal phenotype of the SC5314 strain. These results indicate that TET may inhibit hyphal growth through the Ras1p-cAMP-PKA pathway. In vivo, at a range of concentrations from 4 mg/L to 32 mg/L, TET prolonged the survival of C. albicans-infected Caenorhabditis elegans significantly. This study provides useful information for the development of new strategies to reduce the incidence of C. albicans biofilm-associated infections. - Funding: This work was supported by the National Key Basic Research Program of China (2013CB531602), the National Natural Science Foundation of China (81273558, 81072678 and 90913008), the National Science and Technology Major Project of the Ministry of Science and Technology of China (2011ZX09102-00201), and Shanghai Science and Technology Major Project (10431902200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Candida albicans is the most common fungal pathogen and may cause life-threatening invasive infections, especially in immunocompromised individuals [1,2]. Antifungal agents available are limited in clinic, and drug resistance has become a significant threat [3,4]. C. albicans has a high propensity to develop biofilms on the surfaces of almost any medical devices, such as stents, shunts, prostheses, implants, endotracheal tubes, pacemakers and various types of catheters [5], resulting in biofilm-associated infections [6 8]. More specifically, it is the fourth leading cause of vascular catheter-related infections and the third leading cause of urinary catheter-related infections [912]. Among vascular catheterrelated infections, those due to Candida spp. are associated with the highest rate of mortality [9,13,14]. The C. albicans biofilms are structured microbial communities with C. albicans cells embedded in a matrix of extracellular polymeric substances produced by the cells [1518]. Comparing to planktonic cells, C. albicans cells in biofilms display severe resistance to a wide variety of clinical antifungal agents, including amphotericin B and fluconazole [19 22]. There is an urgent need to develop new antifungal agents against C. albicans biofilms. Tetrandrine (TET) (Fig. 1) is a bis-benzylisoquinoline alkaloid compound originating from several natural plant sources, including Stephania tetrandra [23,24]. This alkaloid displays low toxicity [25] and has been used in China for the treatment of angina, hypertension, silicosis and arthritis [2630]. Besides, TET could reduce acute radiation injury [31,32] and exhibited anti-inflammatory [3234] and anti-tumor [35,36,37,38] activities. In more details, TET was reported to block voltage-gated Ca2+ channels in mammalian cells [38], inhibit NF-kB activation in the alveolar macrophage [33], induce apoptosis and growth arrest in human leukemic HL-60 cells and lung carcinoma cells [36,37], serve as a MDR (multidrug drug resistance) modulator for the treatment of P-glycoprotein-mediated MDR cancers [35]. Interestingly, it exhibited synergistic effect with ketoconazole against drug resistant C. albicans [39] and synergism with econazole against Trichophyton mentagrophytes [40]. Nevertheless, its activity against C. albicans biofilms has not yet been investigated. In this study, we evaluated the activity of TET against C. albicans biofilms, and revealed that the anti-biofilm activity of TET was associated with Ras/cAMP pathway. TET inhibits the formation of C. albicans biofilms in vitro The effect of TET on C. albicans biofilm formation was evaluated (...truncated)


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Lan-Xue Zhao, De-Dong Li, Dan-Dan Hu, Gan-Hai Hu, Lan Yan, Yan Wang, Yuan-Ying Jiang. Effect of Tetrandrine against Candida albicans Biofilms, PLOS ONE, 2013, 11, DOI: 10.1371/journal.pone.0079671