黎巴嫩医院分离的白色念珠菌中 UPC2 突变和唑类抗药性的产生。

IF 3.7 3区 医学 Q2 INFECTIOUS DISEASES
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引用次数: 0

摘要

目的本研究评估了 Upc2 在黎巴嫩住院患者分离的白色念珠菌产生唑类抗药性过程中的作用,并确定了抗药性与毒力之间的相关性:方法:对编码麦角甾醇生物合成调节剂的 UPC2 基因进行了测序,并分析了两株对唑耐药和一株对唑易感的白念珠菌分离株。对 Upc2 进行了氨基酸替代筛选,重点是其配体结合结构域(LBD),已知该结构域与麦角甾醇有相互作用。然后,进行了 Upc2 蛋白二级结构预测和同源建模,随后进行了质膜麦角固醇和细胞壁几丁质的总定量分析。在毒力方面,建立了小鼠全身感染模型,并进行了琼脂粘附和侵袭试验:结果:耐唑分离物在Upc2的LBD中存在新的氨基酸替代,蛋白质二级结构也发生了变化。此外,这些分离物的质膜麦角甾醇含量显著增加。抗性与毒力成反比,而细胞壁几丁质浓度的增加似乎与抗性无关,因为即使我们观察到几丁质浓度的增加,也没有统计学意义:结论:抗偶氮唑的白僵菌分离物在Upc2的LBD中存在新的氨基酸替代,这可能会导致质膜麦角甾醇含量增加,从而阻止偶氮唑与其靶标结合,产生抗药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
UPC2 mutations and development of azole resistance in Candida albicans hospital isolates from Lebanon

Objectives

This study evaluated the role of Upc2 in the development of azole resistance in Candida albicans isolates from Lebanese hospitalized patients and determined a correlation between resistance and virulence.

Methods

The UPC2 gene which codes for an ergosterol biosynthesis regulator was sequenced and analysed in two azole-resistant and one azole-susceptible C. albicans isolates. An amino acid substitution screening was carried out on Upc2 with a focus on its ligand binding domain (LBD) known to interact with ergosterol. Then, Upc2 protein secondary structure prediction and homology modelling were conducted, followed by total plasma membrane ergosterol and cell wall chitin quantifications. For virulence, mouse models of systemic infection were generated and an agar adhesion and invasion test was performed.

Results

Azole-resistant isolates harboured novel amino acid substitutions in the LBD of Upc2 and changes in protein secondary structures were observed. In addition, these isolates exhibited a significant increase in plasma membrane ergosterol content. Resistance and virulence were inversely correlated while increased cell wall chitin concentration does not seem to be linked to resistance since even though we observed an increase in chitin concentration, it was not statistically significant.

Conclusions

The azole-resistant C. albicans isolates harboured novel amino acid substitutions in the LBD of Upc2 which are speculated to induce an increase in plasma membrane ergosterol content, preventing the binding of azoles to their target, resulting in resistance.

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来源期刊
Journal of global antimicrobial resistance
Journal of global antimicrobial resistance INFECTIOUS DISEASES-PHARMACOLOGY & PHARMACY
CiteScore
8.70
自引率
2.20%
发文量
285
审稿时长
34 weeks
期刊介绍: The Journal of Global Antimicrobial Resistance (JGAR) is a quarterly online journal run by an international Editorial Board that focuses on the global spread of antibiotic-resistant microbes. JGAR is a dedicated journal for all professionals working in research, health care, the environment and animal infection control, aiming to track the resistance threat worldwide and provides a single voice devoted to antimicrobial resistance (AMR). Featuring peer-reviewed and up to date research articles, reviews, short notes and hot topics JGAR covers the key topics related to antibacterial, antiviral, antifungal and antiparasitic resistance.
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