High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines.
High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines.
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DOI：
10.1371/journal.pgen.1006374
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发表时间：
2016-11
期刊：
影响因子：
4.5
通讯作者：
Hoepfner D
中科院分区：
文献类型：
--
作者：
Filipuzzi I;Cotesta S;Perruccio F;Knapp B;Fu Y;Studer C;Pries V;Riedl R;Helliwell SB;Petrovic KT;Movva NR;Sanglard D;Tao J;Hoepfner D
全球范围内，真菌病原体侵袭性感染导致的死亡人数超过疟疾。我们在抗真菌筛选中发现了麦角林化合物NGx04，它对哺乳动物细胞具有选择性。高分辨化学基因组学确定脂转移蛋白Sec14p是NGx04的靶标，而Sec14p的化合物耐药突变定义了蛋白质底物结合口袋中的化合物-靶点相互作用。除了在多种致病真菌中具有基本的脂转移功能外，Sec14p还参与分泌对新生隐球菌等真菌致病至关重要的毒力决定因素，使Sec14p成为一个有吸引力的抗真菌靶点。与这一双重功能一致的是，我们证明了NGx04对两个临床分离的新生弧菌的生长具有抑制作用，并且NGx04相关化合物对新生弧菌具有同等甚至更高的效力。此外，NGX04类似物对氟康唑耐药的新生隐球菌具杀菌活性。综上所述，我们提出了NGx04抑制真菌Sec14p的遗传证据，初步数据支持NGx04是一个新的抗真菌起点。新出现的对抗生素的耐药性导致了传染病的不光彩复兴。此外，在过去的30年里，只发现了一个新的抗真菌靶点，用于开发针对真菌的治疗方法。因此，病原体选择靶点和对可能的耐药性决定因素的了解对于成功开发新药是至关重要的。在这里，我们描述了针对脂转移蛋白Sec14p的抗真菌麦角林的鉴定，并抑制了两种致病真菌新生隐球菌的临床分离株的生长。化合物和靶标都代表了进一步研究的吸引力：Sec14P因为它与人类同系物显著不同，并且它与真菌活性和致病性有关，以及麦角林，因为它们在临床上用于治疗各种疾病，证明了有效性和安全性。
Invasive infections by fungal pathogens cause more deaths than malaria worldwide. We found the ergoline compound NGx04 in an antifungal screen, with selectivity over mammalian cells. High-resolution chemogenomics identified the lipid transfer protein Sec14p as the target of NGx04 and compound-resistant mutations in Sec14p define compound-target interactions in the substrate binding pocket of the protein. Beyond its essential lipid transfer function in a variety of pathogenic fungi, Sec14p is also involved in secretion of virulence determinants essential for the pathogenicity of fungi such as Cryptococcus neoformans, making Sec14p an attractive antifungal target. Consistent with this dual function, we demonstrate that NGx04 inhibits the growth of two clinical isolates of C. neoformans and that NGx04-related compounds have equal and even higher potency against C. neoformans. Furthermore NGx04 analogues showed fungicidal activity against a fluconazole resistant C. neoformans strain. In summary, we present genetic evidence that NGx04 inhibits fungal Sec14p and initial data supporting NGx04 as a novel antifungal starting point. Emerging resistance to antibiotics led to an inglorious revival of infectious diseases. Furthermore, in the past 30 years, only one novel anti-fungal target has been discovered which was used to develop therapies against. Therefore pathogen-selective targets and knowledge about possible resistance determinants are of utmost importance to successfully develop new medicines. Here we describe the identification of anti-fungal ergolines, targeting the lipid transfer protein Sec14p, and inhibiting the growth of two clinical isolates of the pathogenic fungus Cryptococcus neoformans. Both, compound and target represent attractive points for further investigations: Sec14p as it differs significantly from the human homolog and as it has been implicated in fungal viability and pathogenicity, and, ergolines as they are used in the clinic against a variety of diseases demonstrating both efficacy and safety.
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