Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.
Design and synthesis of new drugs inhibitors of Candida albicans hyphae and biofilm formation by upregulating the expression of TUP1 transcription repressor gene.
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DOI：
10.1016/j.ejps.2020.105327
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发表时间：
2020-05-30
期刊：
影响因子：
--
通讯作者：
Ibrahim AS
中科院分区：
文献类型：
--
作者：
Hamdy R;Soliman SSM;Alsaadi AI;Fayed B;Hamoda AM;Elseginy SA;Husseiny MI;Ibrahim AS
白色念珠菌是一种常见的人类真菌病原体，可引起从浅表到致命的各种疾病。白色念珠菌以发芽酵母的形式生长，可以在各种环境或生物刺激下转化为菌丝。虽然这两种形式都与毒力有关，但菌丝形式是形成多重耐药生物膜的原因。在这里，新的化合物被设计成选择性地抑制白色念珠菌的菌丝形成，而不影响人类细胞，以提供足够的安全性。新设计的5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one衍生物，命名为SR，显示出非常特异和有效的抑制白色念珠菌菌丝形成的活性。当浓度低于抑制念珠菌、酵母菌和细菌生长所需的浓度时，锶化合物对菌丝的抑制活性为10-40倍。SR化合物的抗菌丝抑制活性是通过激活菌丝转录抑制基因Tup1实现的。Tup1基因的表达与SR化合物活性的相关性研究证实，抗C.SR化合物的白色念珠菌活性是通过抑制菌丝的形成而实现的。新设计的SR化合物对人红细胞的溶血活性为10-40%，而以0.1%Triton为阳性对照的溶血活性为100%。此外，对SR化合物的吸收、分布、代谢、排泄和毒性(ADMET)的理论预测证实了它们的安全性、高效代谢和可能的口服生物利用度。由于新设计的SR化合物的毒性最小，活性显著，未来的药物配方优化可能会开发出一种有前景的菌丝形成抑制剂，不仅适用于白色念珠菌，也适用于其他依赖Tup1的二态真菌感染。
Candida albicans is a common human fungal pathogen that causes disease ranging from superficial to lethal infections. C. albicans grows as budding yeast which can transform into hyphae in response to various environmental or biological stimuli. Although both forms have been associated with virulence, the hyphae form is responsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selectively inhibit C. albicans hyphae formation without affecting human cells to afford sufficient safety. The newly designed 5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one derivatives, named SR, showed very specific and effective inhibition activity against C. albicans hyphae formation. SR compounds caused hyphae inhibition activity at concentrations 10–40 fold lower than the concentration required to inhibit Candida yeast and bacterial growths. The anti-hyphae inhibition activities of SR compounds were via activation of the hyphae transcription repressor gene, TUP1. Correlation studies between the expression of TUP1 gene and the activity of SR compounds confirmed that the anti-C. albicans activities of SR compounds were via inhibition of hyphae formation. The newly designed SR compounds showed 10–40% haemolytic activity on human erythrocytes when compared to 100% haemolysis by 0.1% triton employed as positive control. Furthermore, theoretical prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of SR compounds confirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity and significant activity of the newly-designed SR compounds, a future optimization of pharmaceutical formulation may develop a promising inhibitor of hyphal formation not only for C. albicans but also for other TUP1- dependent dimorphic fungal infections.
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影响因子：
3.2
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
QUORUM SENSING: METHODS AND PROTOCOLS
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1080/07391102.2018.1462734
发表时间：
2019-04-13
影响因子：
4.4
作者：
Cruz, Jorddy N.;Costa, Jose F. S.;Neto, A. M. J. C.
通讯作者：
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