Interaction of Candida albicans Biofilms with Antifungals: Transcriptional Response and Binding of Antifungals to Beta-Glucans
Interaction of Candida albicans Biofilms with Antifungals: Transcriptional Response and Binding of Antifungals to Beta-Glucans
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DOI：
10.1128/aac.01638-09
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发表时间：
2010-05-01
影响因子：
4.9
通讯作者：
d'Enfert, Christophe
中科院分区：
文献类型：
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作者：
Vediyappan, Govindsamy;Rossignol, Tristan;d'Enfert, Christophe
白色念珠菌可以形成生物膜，其对各种抗真菌剂，特别是唑类和多烯类表现出提高的内在抗性。生物膜抗真菌耐药性的分子机制仍然知之甚少。我们已经使用转录谱来探索成熟C.暴露于各种抗真菌剂的白色念珠菌生物膜。成熟角将在连续流动下生长的白色念珠菌生物膜暴露于氟康唑（FLU）、阿替霉素B（AMB）和卡泊芬净（CAS）浓度长达2小时，这些浓度虽然对嗜酸性细胞是致死的，但对生物膜不是致死的。有趣的是，在实验过程中，暴露于Flu的生物膜显示基因表达没有显著变化。在AMB暴露的生物膜中，2.7%的基因表现出改变的表达，而在CAS暴露的生物膜中，13.0%的基因表现出改变的表达。特别是，暴露于CAS导致已知在生物膜形成中起作用的菌丝特异性基因的上调，例如ALS 3和HWP 1。生物膜中的AMB或CAS反应基因与C.白色念珠菌培养物。这些结果表明，C.白念珠菌生物膜对唑类或多烯类的敏感性不是由于暴露于这些抗真菌剂时特定机制的激活，而是由于成熟生物膜的内在性质。在这方面，我们的研究使我们观察到，AMB物理结合C。白色念珠菌生物膜和β-葡聚糖，它们被认为是生物膜细胞外基质的主要成分并阻止唑类到达生物膜细胞。因此，在生物膜生长过程中增强的细胞外基质或β-葡聚糖合成可能会阻止抗真菌剂，如唑类和多烯类，到达生物膜细胞，从而限制它们对这些细胞的毒性和相关的转录反应。
Candida albicans can form biofilms that exhibit elevated intrinsic resistance to various antifungal agents, in particular azoles and polyenes. The molecular mechanisms involved in the antifungal resistance of biofilms remain poorly understood. We have used transcript profiling to explore the early transcriptional responses of mature C. albicans biofilms exposed to various antifungal agents. Mature C. albicans biofilms grown under continuous flow were exposed for as long as 2 h to concentrations of fluconazole (FLU), amphotericin B (AMB), and caspofungin (CAS) that, while lethal for planktonic cells, were not lethal for biofilms. Interestingly, FLU-exposed biofilms showed no significant changes in gene expression over the course of the experiment. In AMB-exposed biofilms, 2.7% of the genes showed altered expression, while in CAS-exposed biofilms, 13.0% of the genes had their expression modified. In particular, exposure to CAS resulted in the upregulation of hypha-specific genes known to play a role in biofilm formation, such as ALS3 and HWP1. There was little overlap between AMB- or CAS-responsive genes in biofilms and those that have been identified as AMB, FLU, or CAS responsive in C. albicans planktonic cultures. These results suggested that the resistance of C. albicans biofilms to azoles or polyenes was due not to the activation of specific mechanisms in response to exposure to these antifungals but rather to the intrinsic properties of the mature biofilms. In this regard, our study led us to observe that AMB physically bound C. albicans biofilms and beta-glucans, which have been proposed to be major constituents of the biofilm extracellular matrix and to prevent azoles from reaching biofilm cells. Thus, enhanced extracellular matrix or beta-glucan synthesis during biofilm growth might prevent antifungals, such as azoles and polyenes, from reaching biofilm cells, thus limiting their toxicity to these cells and the associated transcriptional responses.