The key role of iroBCDN-lacking pLVPK-like plasmid in the evolution of the most prevalent hypervirulent carbapenem-resistant ST11-KL64 Klebsiella pneumoniae in China

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2024-08-14 DOI:10.1016/j.drup.2024.101137

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引用次数: 0

Abstract

Aims

Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP), coharboring hypervirulence and carbapenem-resistance genes mediated by plasmids, causes infections with extremely high mortality and seriously impacts public health. Exploring the transfer mechanisms of virulence/carbapenem-resistance plasmids, as well as the formation and evolution pathway of hv-CRKP is of great significance to the control of hv-CRKP infections.

Methods

In this study, we identified the predominant clone of hv-CRKP in China and elucidated its genomic characteristics and formation route based on 239 multicenter clinical K. pneumoniae isolates and 1014 GenBank genomes by using comparative genomic analysis. Further, we revealed the factors affecting the transfer of virulence plasmids, and explained the genetic foundation for the prevalence of Chinese predominant hv-CRKP clone.

Results

ST11-KL64 is the predominant clone of hv-CRKP in China and primarily evolved from ST11-KL64 CRKP by acquiring the pLVPK-like virulence plasmid from hvKP. Significantly, the virulence gene cluster iroBCDN was lost in the virulence plasmid of ST11-KL64 hv-CRKP but existed in that of hvKP. Moreover, the absence of iroBCDN didn’t decrease the virulence of hv-CRKP, which was proved by bacterial test, cell-interaction test and mice infection model. On the contrary, loss of iroBCDN was observed to regulate virulence/carbapenem-resistance plasmid transfer and oxidative stress-related genes in strains and thus promoted the mobilization of nonconjugative virulence plasmid from hvKP into ST11-KL64 CRKP, forming hv-CRKP which finally had elevated antioxidant capacity and enhanced survival capacity in macrophages. The loss of iroBCDN increased the survival ability of hv-CRKP without decreasing its virulence, endowing it with an evolutionary advantage.

Conclusions

Our work provides new insights into the key role of iroBCDN loss in convergence of CRKP and hvKP, and the genetic and biological foundation for the widespread prevalence of ST11-KL64 hv-CRKP in China.

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缺乏 iroBCDN 的 pLVPK 样质粒在中国最流行的高病毒性碳青霉烯耐药 ST11-KL64 肺炎克雷伯菌进化中的关键作用

目的高病毒性耐碳青霉烯类肺炎克雷伯氏菌（hv-CRKP）具有由质粒介导的高毒力基因和耐碳青霉烯类基因，其感染死亡率极高，严重影响公共卫生。本研究以239株多中心临床肺炎克雷伯分离株和1014株GenBank基因组为基础，通过比较基因组学分析，确定了hv-CRKP在中国的主要克隆，并阐明了其基因组特征和形成途径。结果ST11-KL64是中国最主要的hv-CRKP克隆，主要由ST11-KL64 CRKP通过从hvKP获得pLVPK样毒力质粒进化而来。值得注意的是，ST11-KL64 hv-CRKP的毒力质粒中丢失了毒力基因簇iroBCDN，但在hvKP的毒力质粒中却存在。此外，细菌试验、细胞相互作用试验和小鼠感染模型证明，iroBCDN的缺失并没有降低hv-CRKP的毒力。相反，观察到 iroBCDN 的缺失会调控毒力/碳青霉烯抗性质粒转移和菌株中氧化应激相关基因，从而促进非共轭毒力质粒从 hvKP 转移到 ST11-KL64 CRKP 中，形成 hv-CRKP，最终提高抗氧化能力，增强在巨噬细胞中的存活能力。我们的工作为 iroBCDN 缺失在 CRKP 和 hvKP 融合过程中的关键作用，以及 ST11-KL64 hv-CRKP 在中国广泛流行的遗传和生物学基础提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research