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.
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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)