在卡泊芬净治疗期间,肠道定植念珠菌的进化动态:鞘脂生物合成中出现具有临床意义的突变

IF 6.7 1区 医学 Q1 Immunology and Microbiology
Yasmine Hassoun, Ariel A. Aptekmann, Mikhail V. Keniya, Rosa Y. Gomez, Nicole Alayo, Giovanna Novi, Christopher Quinteros, Firat Kaya, Matthew Zimmerman, Diego H. Caceres, Nancy A. Chow, David S. Perlin, Erika Shor
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引用次数: 0

摘要

侵袭性真菌感染死亡率很高,而抗真菌药物种类有限和抗真菌药物耐药性不断增加又加剧了这一问题。棘白菌素类是以真菌细胞壁生物合成酶β-葡聚糖合成酶(GS)为靶点的一线抗真菌药物。棘白菌素类药物的耐药性一般较低,但在一些菌种(如定植于人体粘膜表面的机会性酵母病原体--光滑念珠菌)中的耐药性却在不断增加。GS编码基因(C. glabrata中的FKS1和FKS2)的突变与临床棘白菌素失效密切相关,但流行病学研究表明,其他尚未确定的因素也会影响对棘白菌素的敏感性。此外,虽然已知肠道是耐药菌株出现的重要贮藏库,但对耐药性的进化却不甚了解。在此,我们研究了免疫功能正常的小鼠在接受卡泊芬净(一种广泛使用的棘白菌素)治疗期间,其肠道中胶孢子菌的进化动态。全基因组和扩增片段测序显示,在治疗过程中,草履虫群体的基因迅速多样化,并出现了药物靶标(FKS2)和非药物靶标突变,后者主要出现在编码脂肪酸伸长酶的 FEN1 基因中,该基因在鞘脂生物合成中起作用。在卡泊芬净处理期间,fen1突变体在肠道中表现出较高的适应性,并含有较高水平的植物鞘磷脂,而通过删除YPC1基因对植物鞘磷脂进行遗传耗竭,可使野生型菌株对卡泊芬净过敏,并与fen1Δ具有表观关系。此外,高分辨率成像和质谱分析表明,fen1Δ细胞对卡泊芬净的敏感性降低与卡泊芬净与质膜的结合减少有关。最后,我们在临床上发现了几种不同的fen1突变,它们与fen1Δ突变体表型相同,导致对卡泊芬净的敏感性降低。这些研究揭示了临床上对卡泊芬净敏感性的新的遗传和分子决定因素,并阐明了药物靶标和非药物靶标突变的动态演化,这些突变降低了定植有青霉藻患者的棘球蚴素疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis
Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting β-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like Candida glabrata, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (FKS1 and FKS2 in C. glabrata) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of C. glabrata colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this C. glabrata population during treatment and the emergence of both drug target (FKS2) and non-drug target mutations, the latter predominantly in the FEN1 gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The fen1 mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of YPC1 gene hypersensitized the wild type strain to caspofungin and was epistatic to fen1Δ. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in fen1Δ cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different fen1 mutations in clinical C. glabrata isolates, which phenocopied the fen1Δ mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with C. glabrata.
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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