Identification and functional characterization of Penicillium marneffei pleiotropic drug resistance transporters ABC1 and ABC2
Identification and functional characterization of Penicillium marneffei pleiotropic drug resistance transporters ABC1 and ABC2
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DOI：
10.1093/mmy/myv117
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发表时间：
2016-07-01
期刊：
影响因子：
2.9
通讯作者：
Kajiwara, Susumu
中科院分区：
文献类型：
--
作者：
Panapruksachat, Siribun;Iwatani, Shun;Kajiwara, Susumu
由双相真菌马尔尼菲青霉菌引起的青霉病是一种地方性的、艾滋病定义的疾病，并且是热带东南亚艾滋病患者的第三大常见机会性感染，仅次于结核病和隐球菌病。未经治疗的患者预后不良;然而，主要的阿替霉素B治疗后，延长伊曲康唑预防是有效的。为了鉴定可能在马尔尼菲青霉潜在的多药耐药中起作用的ATP结合盒（ABC）转运蛋白，我们从基因组序列中鉴定并分类了所有46种马尔尼菲青霉ABC转运蛋白。PmABC 1和PmABC 2与原型白色念珠菌多药外排泵基因CDR 1最相似。马尔尼菲青霉Abc 1 p（PmAbc 1 p）在酿酒酵母中功能性表达，尽管水平相当低，并正确定位于质膜，导致细胞对唑类和许多其他外源性物质的抗性比未转化的细胞高4倍至8倍。马尔尼菲青霉Abc 2 p（PmAbc 2 p）以类似的低水平表达，但它没有外排活性并且没有适当地定位于质膜。有趣的是，当细胞转移到37时，PmAbc 1 p错误定位并失去了转运活性。C.结论PmAbc 1 p在S.酿酒酵母赋予几种外源性物质的耐药性，表明PmAbc 1 p可能是一种多药外排泵。
Penicilliosis caused by the dimorphic fungus Penicillium marneffei is an endemic, AIDS-defining illness and, after tuberculosis and cryptococcosis, the third most common opportunistic infection of AIDS patients in tropical Southeast Asia. Untreated, patients have poor prognosis; however, primary amphotericin B treatment followed by prolonged itraconazole prophylaxis is effective. To identify ATP-binding cassette (ABC) transporters that may play a role in potential multidrug resistance of P. marneffei, we identified and classified all 46 P. marneffei ABC transporters from the genome sequence. PmABC1 and PmABC2 were most similar to the archetype Candida albicans multidrug efflux pump gene CDR1. P. marneffei Abc1p (PmAbc1p) was functionally expressed in Saccharomyces cerevisiae, although at rather low levels, and correctly localized to the plasmamembrane, causing cells to be fourfold to eightfold more resistant to azoles and many other xenobiotics than untransformed cells. P. marneffei Abc2p (PmAbc2p) was expressed at similarly low levels, but it had no efflux activity and did not properly localize to the plasma membrane. Interestingly, PmAbc1p mislocalized and lost its transport activity when cells were shifted to 37. C. We conclude that expression of PmAbc1p in S. cerevisiae confers resistance to several xenobiotics indicating that PmAbc1p may be a multidrug efflux pump.