携带 mcr-9 的耐碳青霉烯类肠杆菌对多粘菌素的诱导抗性转录组分析。

IF 3.7 3区 医学 Q2 INFECTIOUS DISEASES Journal of global antimicrobial resistance Pub Date : 2024-06-01 DOI:10.1016/j.jgar.2024.04.006
Jiming Wu , Longjin Liu , Jianmin Wang , Ying Wang , Xinhui Li , Xiaoyu Wang , Shan Jiang , Wengang Li , Jisheng Zhang , Xiaoli Zhang
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引用次数: 0

摘要

目的:多粘菌素是目前治疗多重耐药革兰氏阴性菌感染的最后手段,但质粒介导的移动多粘菌素耐药基因(mcr)威胁着多粘菌素的疗效,尤其是在耐碳青霉烯类肠杆菌复合菌(CRECC)中。本研究旨在深入了解多粘菌素诱导细菌耐药性的机制以及过表达 mcr-9 的影响:方法:用梯度浓度的多粘菌素处理携带 mcr-9 基因的临床菌株 CRECC414。随后,采用肉汤微稀释法确定最低抑菌浓度(MIC),并利用 RT-qPCR 评估 mcr-9 的表达。利用转录组测序和全基因组测序(WGS)确定菌株中因多粘菌素抗性增强而产生的变化,并分析显著的转录组差异,同时在基因组水平上对代谢网络进行全面检查:结果:多粘菌素处理可诱导 mcr-9 表达上调,并显著提高菌株的 MIC。此外,WGS 和转录组结果显示,arnBCADTEF 基因盒显著上调,表明 Arn/PhoPQ 系统介导的 L-Ara4N 修饰是获得高水平抗性的首选机制。此外,还观察到细菌在多药外排泵、氧化应激和修复机制、细胞膜生物合成以及碳水化合物代谢途径方面的基因表达发生了重大变化:结论:多粘菌素极大地破坏了重要细胞途径的转录。尽管 mcr-9 高表达,但完整的 PhoPQ 双组分系统是泄殖腔肠杆菌耐多粘菌素的先决条件。这些发现为进一步研究 CRECC 的多粘菌素抗性提供了新的重要信息。
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Transcriptomic analysis of induced resistance to polymyxin in carbapenem-resistant Enterobacter cloacae complex isolate carrying mcr-9

Objectives

Polymyxins are currently the last-resort treatment against multi-drug resistant Gram-negative bacterial infections, but plasmid-mediated mobile polymyxin resistance genes (mcr) threaten its efficacy, especially in carbapenem-resistant Enterobacter cloacae complex (CRECC). The objective of this study was to provide insights into the mechanism of polymyxin-induced bacterial resistance and the effect of overexpression of mcr-9.

Methods

The clinical strain CRECC414 carrying the mcr-9 gene was treated with a gradient concentration of polymyxin. Subsequently, the broth microdilution was used to determine the minimum inhibitory concentration (MIC) and RT-qPCR was utilized to assess mcr-9 expression. Transcriptome sequencing and whole genome sequencing (WGS) was utilized to identify alterations in strains resulting from increased polymyxin resistance, and significant transcriptomic differences were analysed alongside a comprehensive examination of metabolic networks at the genomic level.

Results

Polymyxin treatment induced the upregulation of mcr-9 expression and significantly elevated the MIC of the strain. Furthermore, the WGS and transcriptomic results revealed a remarkable up-regulation of arnBCADTEF gene cassette, indicating that the Arn/PhoPQ system-mediated L-Ara4N modification is the preferred mechanism for achieving high levels of resistance. Additionally, significant alterations in bacterial gene expression were observed with regards to multidrug efflux pumps, oxidative stress and repair mechanisms, cell membrane biosynthesis, as well as carbohydrate metabolic pathways.

Conclusion

Polymyxin greatly disrupts the transcription of vital cellular pathways. A complete PhoPQ two-component system is a prerequisite for polymyxin resistance of Enterobacter cloacae, even though mcr-9 is highly expressed. These findings provide novel and important information for further investigation of polymyxin resistance of CRECC.

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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.
期刊最新文献
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