Calcium-activated-calcineurin reduces the In vitro and In vivo sensitivity of fluconazole to Candida albicans via Rta2p.
Calcium-activated-calcineurin reduces the In vitro and In vivo sensitivity of fluconazole to Candida albicans via Rta2p.
复制标题
DOI：
10.1371/journal.pone.0048369
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jiang YY
中科院分区：
文献类型：
--
作者：
Jia Y;Tang RJ;Wang L;Zhang X;Wang Y;Jia XM;Jiang YY
由于耐药性的出现，氟康唑（FLC）一线治疗念珠菌血症越来越多地导致临床失败。我们前期的研究发现RTA 2参与了钙调神经磷酸酶介导的C.白色念珠菌在本研究中，我们发现钙激活的钙调神经磷酸酶显著降低了C。通过Rta2p阻断FLC对质膜的损伤，从而抑制FLC对白念珠菌的杀伤作用。此外，我们发现RTA 2本身并不参与C.白念珠菌毒力，但RTA 2的破坏显着增加FLC在小鼠模型中的治疗效果的系统性念珠菌病。相反，一个RTA 2等位基因的重新引入和RTA 2的异位表达都显著降低了哺乳动物宿主中的FLC功效。最后，我们发现，钙激活的钙调神经磷酸酶，通过其目标Rta2p，显着降低FLC对念珠菌血症的疗效。鉴于Rta2p在控制FLC疗效中的关键作用，Rta2p可能是抗真菌治疗的潜在药物靶标。
Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.
登录
查看更多内容
影响因子：
11.8
作者：
Horn, David L.;Neofytos, Dionissios;Webster, Karen M.
通讯作者：
Webster, Karen M.
影响因子：
4.9
作者：
Gamarra, Soledad;Rocha, Elousa Maria F.;Perlin, David S.
通讯作者：
Perlin, David S.
影响因子：
6.7
作者：
Cowen LE
通讯作者：
Cowen LE
影响因子：
6.7
作者：
Epp E;Vanier G;Harcus D;Lee AY;Jansen G;Hallett M;Sheppard DC;Thomas DY;Munro CA;Mullick A;Whiteway M
通讯作者：
Whiteway M
影响因子：
4.8
作者：
Gaigg, B;Timischl, B;Schneiter, R
通讯作者：
Schneiter, R