Novel Nystatin A1 derivatives exhibiting low host cell toxicity and antifungal activity in an in vitro model of oral candidosis
Novel Nystatin A1 derivatives exhibiting low host cell toxicity and antifungal activity in an in vitro model of oral candidosis
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DOI：
10.1007/s00430-014-0343-4
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Williams, David W.
中科院分区：
文献类型：
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作者：
Boros-Majewska, Joanna;Salewska, Natalia;Williams, David W.
由白色念珠菌引起的真菌性口腔感染是免疫功能低下患者的常见问题。由于可用的抗真菌药物数量少、毒性相对较高以及抗真菌药物耐药性的出现，此类感染的管理受到限制。鉴于这些问题，我们的研究集中在抗真菌抗生素制霉菌素A（1）的新型衍生物上，通过对该分子的氨基进行修饰而产生。本研究的目的是使用基于重建的人口腔上皮（RHOE）的口腔念珠菌病体外模型来评估这些新化合物的抗真菌有效性和宿主细胞毒性。最初的研究采用肉汤微量稀释法，揭示了对嗜酸性C。制霉菌素A（1）的最小抑菌浓度低于新衍生物。然而，制霉菌素A（1）对人角质形成细胞的毒性也明显更强。有趣的是，使用活/死染色来评估C.在RHOE感染后，制霉菌素A（1）衍生物对白色念珠菌和组织细胞活力的影响，制霉菌素A（1）衍生物对念珠菌的活性比母体药物更高，对上皮细胞的毒性更低。RHOE释放的乳酸脱氢酶活性表明，与制霉菌素A相比，使用某些制霉菌素衍生物时，组织损伤减少了四倍（1）。此外，与制霉菌素A（1）相比，C.新的多烯显著降低了白色念珠菌的数量。在无抗真菌药物的情况下，激光共聚焦扫描显微镜显示C。白色念珠菌广泛侵入RHOE。然而，新衍生物的存在大大减少或完全阻止了这种真菌入侵。
Opportunistic oral infections caused by Candida albicans are frequent problems in immunocompromised patients. Management of such infections is limited due to the low number of antifungal drugs available, their relatively high toxicity and the emergence of antifungal resistance. Given these issues, our investigations have focused on novel derivatives of the antifungal antibiotic Nystatin A(1), generated by modifications at the amino group of this molecule. The aims of this study were to evaluate the antifungal effectiveness and host cell toxicity of these new compounds using an in vitro model of oral candidosis based on a reconstituted human oral epithelium (RHOE). Initial studies employing broth microdilution, revealed that against planktonic C. albicans, Nystatin A(1) had lower minimal inhibitory concentration than novel derivatives. However, Nystatin A(1) was also markedly more toxic against human keratinocyte cells. Interestingly, using live/dead staining to assess C. albicans and tissue cell viability after RHOE infection, Nystatin A(1) derivatives were more active against Candida with lower toxicity to epithelial cells than the parent drug. Lactate dehydrogenase activity released by the RHOE indicated a fourfold reduction in tissue damage when certain Nystatin derivatives were used compared with Nystatin A(1). Furthermore, compared with Nystatin A(1), colonisation of the oral epithelium by C. albicans was notably reduced by the new polyenes. In the absence of antifungal agents, confocal laser scanning microscopy showed that C. albicans extensively invaded the RHOE. However, the presence of the novel derivatives greatly reduced or totally prevented this fungal invasion.