Bari Vinay K, Sharma Sushma, Alfatah Md, Mondal Alok K, Ganesan K
CSIR-Institute of Microbial Technology, Sector 39-A, Chandigarh - 160036, India.
Sci Rep. 2015 May 12;5:9685. doi: 10.1038/srep09685.
Invasive opportunistic fungal infections of humans are common among those suffering from impaired immunity, and are difficult to treat resulting in high mortality. Amphotericin B (AmB) is one of the few antifungals available to treat such infections. The AmB resistance mechanisms reported so far mainly involve decrease in ergosterol content or alterations in cell wall. In contrast, depletion of sphingolipids sensitizes cells to AmB. Recently, overexpression of PMP3 gene, encoding plasma membrane proteolipid 3 protein, was shown to increase and its deletion to decrease, AmB resistance. Here we have explored the mechanistic basis of PMP3 effect on AmB resistance. It was found that ergosterol content and cell wall integrity are not related to modulation of AmB resistance by PMP3. A few prominent phenotypes of PMP3 delete strain, namely, defective actin polarity, impaired salt tolerance, and reduced rate of endocytosis are also not related to its AmB-sensitivity. However, PMP3 overexpression mediated increase in AmB resistance requires a functional sphingolipid pathway. Moreover, AmB sensitivity of strains deleted in PMP3 can be suppressed by the addition of phytosphingosine, a sphingolipid pathway intermediate, confirming the importance of this pathway in modulation of AmB resistance by PMP3.
侵袭性人类机会性真菌感染在免疫功能受损者中很常见，且难以治疗，导致高死亡率。两性霉素B（AmB）是可用于治疗此类感染的少数抗真菌药物之一。迄今为止报道的AmB耐药机制主要涉及麦角甾醇含量降低或细胞壁改变。相反，鞘脂的消耗会使细胞对AmB敏感。最近，编码质膜蛋白脂质3蛋白的PMP3基因的过表达显示会增加AmB耐药性，而其缺失则会降低AmB耐药性。在此，我们探讨了PMP3影响AmB耐药性的机制基础。发现麦角甾醇含量和细胞壁完整性与PMP3对AmB耐药性的调节无关。PMP3缺失菌株的一些显著表型，即肌动蛋白极性缺陷、耐盐性受损和内吞作用速率降低，也与其对AmB的敏感性无关。然而，PMP3过表达介导的AmB耐药性增加需要功能性鞘脂途径。此外，添加鞘脂途径中间体植物鞘氨醇可抑制PMP3缺失菌株的AmB敏感性，证实了该途径在PMP3调节AmB耐药性中的重要性。
