一种新型抗真菌剂对白色念珠菌生物膜具有活性，并在体外抑制致突变性乙醛的产生。
A novel antifungal is active against Candida albicans biofilms and inhibits mutagenic acetaldehyde production in vitro.
作者信息
Nieminen Mikko T, Novak-Frazer Lily, Rautemaa Vilma, Rajendran Ranjith, Sorsa Timo, Ramage Gordon, Bowyer Paul, Rautemaa Riina
机构信息
Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland; Department of Periodontology, Institute of Dentistry, University of Helsinki, Helsinki, Finland; Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
The University of Manchester, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, United Kingdom.
出版信息
PLoS One. 2014 May 27;9(5):e97864. doi: 10.1371/journal.pone.0097864. eCollection 2014.
The ability of C. albicans to form biofilms is a major virulence factor and a challenge for management. This is evident in biofilm-associated chronic oral-oesophageal candidosis, which has been shown to be potentially carcinogenic in vivo. We have previously shown that most Candida spp. can produce significant levels of mutagenic acetaldehyde (ACH). ACH is also an important mediator of candidal biofilm formation. We have also reported that D,L-2-hydroxyisocaproic acid (HICA) significantly inhibits planktonic growth of C. albicans. The aim of the present study was to investigate the effect of HICA on C. albicans biofilm formation and ACH production in vitro. Inhibition of biofilm formation by HICA, analogous control compounds or caspofungin was measured using XTT to measure biofilm metabolic activity and PicoGreen as a marker of biomass. Biofilms were visualised by scanning electron microscopy (SEM). ACH levels were measured by gas chromatography. Transcriptional changes in the genes involved in ACH metabolism were measured using RT-qPCR. The mean metabolic activity and biomass of all pre-grown (4, 24, 48 h) biofilms were significantly reduced after exposure to HICA (p<0.05) with the largest reductions seen at acidic pH. Caspofungin was mainly active against biofilms pre-grown for 4 h at neutral pH. Mutagenic levels (>40 µM) of ACH were detected in 24 and 48 h biofilms at both pHs. Interestingly, no ACH production was detected from D-glucose in the presence of HICA at acidic pH (p<0.05). Expression of genes responsible for ACH catabolism was up-regulated by HICA but down-regulated by caspofungin. SEM showed aberrant hyphae and collapsed hyphal structures during incubation with HICA at acidic pH. We conclude that HICA has potential as an antifungal agent with ability to inhibit C. albicans cell growth and biofilm formation. HICA also significantly reduces the mutagenic potential of C. albicans biofilms, which may be important when treating bacterial-fungal biofilm infections.
白色念珠菌形成生物膜的能力是一个主要的毒力因子，也是治疗中的一项挑战。这在与生物膜相关的慢性口腔 - 食管念珠菌病中很明显，该病已被证明在体内具有潜在致癌性。我们之前已经表明，大多数念珠菌属都能产生大量具有致突变性的乙醛（ACH）。ACH也是念珠菌生物膜形成的重要介质。我们还报告过，D，L - 2 - 羟基异己酸（HICA）能显著抑制白色念珠菌的浮游生长。本研究的目的是在体外研究HICA对白色念珠菌生物膜形成和ACH产生的影响。使用XTT测量生物膜代谢活性以及用PicoGreen作为生物量标记物，来检测HICA、类似对照化合物或卡泊芬净对生物膜形成的抑制作用。通过扫描电子显微镜（SEM）观察生物膜。用气相色谱法测量ACH水平。使用RT - qPCR测量参与ACH代谢的基因的转录变化。暴露于HICA后，所有预培养（4、24、48小时）生物膜的平均代谢活性和生物量均显著降低（p<0.05），在酸性pH条件下降低幅度最大。卡泊芬净主要对在中性pH下预培养4小时的生物膜有活性。在两个pH值下，24小时和48小时的生物膜中均检测到致突变水平（>40 µM）的ACH。有趣的是，在酸性pH条件下，在HICA存在时，未检测到D - 葡萄糖产生ACH（p<0.05）。HICA上调了负责ACH分解代谢的基因的表达，但卡泊芬净使其下调。SEM显示，在酸性pH条件下与HICA孵育期间，菌丝异常且菌丝结构塌陷。我们得出结论，HICA有潜力作为一种抗真菌剂，具有抑制白色念珠菌细胞生长和生物膜形成的能力。HICA还显著降低了白色念珠菌生物膜的致突变潜力，这在治疗细菌 - 真菌生物膜感染时可能很重要。
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