棘白菌素和ibrexafungerp处理的光秃假丝酵母的n-seq筛选揭示了抗真菌和交叉耐药的途径。

IF 3.7 2区 生物学 Q2 MICROBIOLOGY
mSphere Pub Date : 2025-07-07 DOI:10.1128/msphere.00270-25
Timothy J Nickels, Kyle W Cunningham
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引用次数: 0

摘要

光秃念珠菌(也称为光秃中丝酵母菌)是念珠菌病的第二大常见原因,仅次于白色念珠菌,由于内在和获得性抗真菌耐药性机制,患病率正在上升。本研究利用转座子诱变和深度测序(n-seq)技术探讨了BG2菌株对四种不同棘球白素(micafungin, anidulafungin, rezafungin和caspofungin)和β -1,3-葡聚糖合成酶(GS)的非棘球白素抑制剂(ibrexafungerp)的耐药机制。与其他抗真菌药物不同,caspofungin对鞘脂基因的敏感性较高,对线粒体基因的依赖性较低。线粒体基因的许多缺陷增加了micafungin、anidulafungin、rezafungin和ibrexafungerp的适应性,主要是通过对Pdr1的影响,Pdr1是一种已知的促进氟康唑抗性的应激激活转录因子。Pdr1的几个靶点(RTA1、LAF1、LAC1、IPT1和RSB1)在单独过表达时改变了对一种或多种GS抑制剂的耐药性。尽管Gal11和介质复合物的其他亚基对于Pdr1的作用是必需的,但Gal11的抑制剂(ikx1)由于脱靶拮抗作用而不能与micafungin协同作用。不同GS抑制剂的遗传抗性谱在BG2菌株背景下以及与CBS138菌株背景的比较中均存在较大差异。菌株内的变异与基因缺陷有关,基因缺陷被认为会改变磷脂和麦角甾醇的组成或细胞膜的不对称。这些发现通常支持并扩展了先前的假设,即脂质密码控制着光棘草的GS抑制和抗真菌敏感性。棘白菌素和白藜芦醇是针对同一种真菌酶的重要抗真菌药物。当真菌对其中一种抗真菌药物产生抗性时,它可能会或可能不会对其他抗真菌药物产生交叉抗性。本研究探讨了致病酵母菌秃念珠菌的每个基因如何对这五种抗真菌药物产生抗性和交叉抗性。它为了解每种抗真菌药物如何与靶酶相互作用提供了新的见解,并确定了交叉耐药常见或罕见的抗真菌药物,为可能在临床环境中最有效的序列和组合提供了指导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tn-seq screens in Candida glabrata treated with echinocandins and ibrexafungerp reveal pathways of antifungal resistance and cross-resistance.

Candida glabrata (also known as Nakaseomyces glabratus) is the second most common cause of candidiasis, next to Candida albicans, and is rising in prevalence due to intrinsic and acquired mechanisms of antifungal resistance. This study utilizes transposon mutagenesis and deep sequencing (Tn-seq) to explore mechanisms of resistance to four different echinocandins (micafungin, anidulafungin, rezafungin, and caspofungin) and a non-echinocandin inhibitor (ibrexafungerp) of beta-1,3-glucan synthase (GS) in the BG2 strain background. Contrary to the other antifungals, caspofungin susceptibility exhibited high dependence on sphingolipid genes and low dependence on mitochondrial genes. Numerous deficiencies in mitochondrial genes increased fitness in micafungin, anidulafungin, rezafungin, and ibrexafungerp largely through effects on Pdr1, a stress-activated transcription factor known to promote fluconazole resistance. Several targets of Pdr1 (RTA1, LAF1, LAC1, IPT1, and RSB1) altered resistance to one or more of the GS inhibitors when overexpressed individually. Though Gal11 and other subunits of the mediator complex were necessary for the Pdr1 effects, an inhibitor of Gal11 (iKIX1) did not synergize with micafungin due to off-target antagonistic effects. Substantial variation was observed in the genetic resistance spectra for the different GS inhibitors within the BG2 strain background and comparison to the CBS138 strain background. The intra-strain variation was linked to gene deficiencies thought to alter phospholipid and ergosterol composition or asymmetry in cellular membranes. The findings generally support and extend earlier hypotheses that a lipid code governs GS inhibition and antifungal susceptibility in C. glabrata.IMPORTANCEEchinocandins and ibrexafungerp are important antifungals that target the same fungal enzyme. When the fungus acquires resistance to one of these antifungals, it may or may not exhibit cross-resistance to the others. This study investigates how every gene in the pathogenic yeast Candida glabrata contributes to resistance and cross-resistance to all five antifungals of this type. It offers new insights into how each antifungal interacts with the target enzyme and identifies the antifungals where cross-resistance is common or rare, providing guidance on the sequences and combinations that may be most effective in clinical settings.

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来源期刊
mSphere
mSphere Immunology and Microbiology-Microbiology
CiteScore
8.50
自引率
2.10%
发文量
192
审稿时长
11 weeks
期刊介绍: mSphere™ is a multi-disciplinary open-access journal that will focus on rapid publication of fundamental contributions to our understanding of microbiology. Its scope will reflect the immense range of fields within the microbial sciences, creating new opportunities for researchers to share findings that are transforming our understanding of human health and disease, ecosystems, neuroscience, agriculture, energy production, climate change, evolution, biogeochemical cycling, and food and drug production. Submissions will be encouraged of all high-quality work that makes fundamental contributions to our understanding of microbiology. mSphere™ will provide streamlined decisions, while carrying on ASM''s tradition for rigorous peer review.
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