Antifungal Activity of Novel Formulations Based on Terpenoid Prodrugs against C. albicans in a Mouse Model.
Antifungal Activity of Novel Formulations Based on Terpenoid Prodrugs against C. albicans in a Mouse Model.
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DOI：
10.3390/pharmaceutics13050633
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发表时间：
2021-04-29
期刊：
影响因子：
5.4
通讯作者：
Billack B
中科院分区：
文献类型：
--
作者：
Menon S;Liang X;Vartak R;Patel K;Di Stefano A;Cacciatore I;Marinelli L;Billack B
香芹酚（Carvacrol，CAR）是一种酚类单萜化合物，其抗菌和抗真菌活性已被广泛研究。由于其不良的物理化学性质，先前合成了具有改善的水溶性的水溶性香芹酚前药（WSCP），并发现其具有抗菌活性。在此，针对氟康唑（FLU）敏感和耐药菌株测试了三种新型CAR类似物，WSCP 1、WSCP 2和WSCP 3，其中它们显示出比CAR更大的抗真菌活性。白色念珠菌研究了CAR前药发挥抗真菌活性的可能机制。培养基酸化试验的结果表明，CAR及其合成设计的前药抑制酵母质膜H+-ATP酶（Pma 1 p），这是真菌中的一个重要靶标。换句话说，体外数据表明，考虑到其改善的水溶性，CAR类似物可以证明是CAR的更好替代品。此外，CAR和WSCP 1被开发成阴道内制剂，并在外阴阴道念珠菌病（VVC）的小鼠模型中以50 mg/kg的测试剂量施用。尽管CAR和WSCP 1制剂在VVC小鼠模型中均表现出抗真菌功效，但WSCP 1制剂上级CAR，与对照组（感染、未治疗的动物）相比，感染显着减少约120倍。综上所述，合成设计的CAR前药，即WSCP 1，被证明是一种可能的解决方案，用于水溶性差的药物，体外必需酵母泵的抑制剂和体内有效且有前途的抗真菌剂。
Carvacrol (CAR), a phenolic monoterpenoid, has been extensively investigated for its antimicrobial and antifungal activity. As a result of its poor physicochemical properties, water soluble carvacrol prodrugs (WSCPs) with improved water solubility were previously synthesized and found to possess antimicrobial activity. Here, three novel CAR analogs, WSCP1, WSCP2, and WSCP3, were tested against fluconazole (FLU)-sensitive and -resistant strains where they showed greater antifungal activity than CAR against C. albicans. The probable mechanism by which the CAR prodrugs exert the antifungal activity was studied. Results from medium acidification assays demonstrated that the CAR and its synthetically designed prodrugs inhibit the yeast plasma membrane H+-ATPase (Pma1p), an essential target in fungi. In other words, in vitro data indicated that CAR analogs can prove to be a better alternative to CAR considering their improved water solubility. In addition, CAR and WSCP1 were developed into intravaginal formulations and administered at test doses of 50 mg/kg in a mouse model of vulvovaginal candidiasis (VVC). Whereas the CAR and WSCP1 formulations both exhibited antifungal efficacy in the mouse model of VVC, the WSCP1 formulation was superior to CAR, showing a remarkable decrease in infection by ~120-fold compared to the control (infected, untreated animals). Taken together, a synthetically designed prodrug of CAR, namely WSCP1, proved to be a possible solution for poorly water-soluble drugs, an inhibitor of an essential yeast pump in vitro and an effective and promising antifungal agent in vivo.
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DOI：
10.3390/ph10040086
发表时间：
2017-11-02
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Nazzaro F;Fratianni F;Coppola R;Feo V
通讯作者：
Feo V
DOI：
10.1590/s0036-46652008000100002
发表时间：
2008-02-01
期刊：
Revista do Instituto de Medicina Tropical de São Paulo
影响因子：
--
作者：
Koga-Ito, Cristiane Yumi;Lyon, Juliana Pereira;Resende, Maria Aparecida de
通讯作者：
Resende, Maria Aparecida de
影响因子：
--
作者：
Conti, Heather R;Huppler, Anna R;Whibley, Natasha;Gaffen, Sarah L
通讯作者：
Gaffen, Sarah L
影响因子：
4.9
作者：
Perea, S;López-Ribot, JL;Patterson, TF
通讯作者：
Patterson, TF
影响因子：
3.1
作者：
Fidel, PL;Cutright, J;Steele, C
通讯作者：
Steele, C