Scholarlink

Purpose <p>Carbapenem-resistant <i>Enterobacter cloacae</i> complex (CRECC) has become an increasingly important pathogen in healthcare-associated infections, with limited treatment options and a high mortality rate. As reports of antimicrobial resistance continue to rise, tigecycline (TGC) and ceftazidime-avibactam (CZA) have emerged as the last-line therapies for CRECC infections. The aim of this study was to investigate collateral sensitivity to ceftazidime-avibactam following the acquisition of tigecycline resistance in NDM-producing CRECC, and to explore the transcriptional changes associated with this phenomenon and propose potential mechanistic hypotheses.</p> Methods <p>Antimicrobial susceptibility profiles were determined using the broth microdilution method, and changes in colony morphology were analyzed. Transcriptomic sequencing was performed to characterize global gene expression alterations associated with antimicrobial resistance, and an in vivo <i>Galleria mellonella</i> infection model was used to assess the virulence of the mutant strains.</p> Results <p>Both drug-resistant mutants displayed a stable mucoid phenotype with marked collateral susceptibility to CZA, with minimum inhibitory concentrations decreasing from greater than 128&#xa0;mg/L to 0.5–1&#xa0;mg/L. Compared with the parental strains, these mutants showed thickened cell surface structures, impaired growth, reduced serum tolerance, and significantly attenuated virulence in the <i>Galleria mellonella</i> infection model. Transcriptomic analysis revealed marked downregulation of metallo-<i>β</i>-lactamase-related genes at the transcriptional level.</p> Conclusion <p>In this study of two clinical isolates, collateral sensitivity to CZA was associated with transcriptional downregulation of <i>bla</i><sub>NDM</sub> and altered bacterial metabolism. These findings suggest a potential trade-off between tigecycline resistance and CZA susceptibility that warrants further functional validation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Transcriptomic correlates of ceftazidime-avibactam collateral sensitivity in tigecycline-resistant NDM-producing enterobacter cloacae complex

  • 期刊论文

  • 发表日期：

    2026年5月25日

查看全文
  • Luyao Tian,
  • Jiming Wu,
  • Youtao Liang,
  • Xushan Liang,
  • Jin Wang,
  • Shijian Chen,
  • Mingjing Liao,
  • Chenchen Liu,
  • Yuhui Chen,
  • Jianmin Wang,
  • Chunjiang Li,
  • Xiaoli Zhang

摘要

Purpose

Carbapenem-resistant Enterobacter cloacae complex (CRECC) has become an increasingly important pathogen in healthcare-associated infections, with limited treatment options and a high mortality rate. As reports of antimicrobial resistance continue to rise, tigecycline (TGC) and ceftazidime-avibactam (CZA) have emerged as the last-line therapies for CRECC infections. The aim of this study was to investigate collateral sensitivity to ceftazidime-avibactam following the acquisition of tigecycline resistance in NDM-producing CRECC, and to explore the transcriptional changes associated with this phenomenon and propose potential mechanistic hypotheses.

Methods

Antimicrobial susceptibility profiles were determined using the broth microdilution method, and changes in colony morphology were analyzed. Transcriptomic sequencing was performed to characterize global gene expression alterations associated with antimicrobial resistance, and an in vivo Galleria mellonella infection model was used to assess the virulence of the mutant strains.

Results

Both drug-resistant mutants displayed a stable mucoid phenotype with marked collateral susceptibility to CZA, with minimum inhibitory concentrations decreasing from greater than 128 mg/L to 0.5–1 mg/L. Compared with the parental strains, these mutants showed thickened cell surface structures, impaired growth, reduced serum tolerance, and significantly attenuated virulence in the Galleria mellonella infection model. Transcriptomic analysis revealed marked downregulation of metallo-β-lactamase-related genes at the transcriptional level.

Conclusion

In this study of two clinical isolates, collateral sensitivity to CZA was associated with transcriptional downregulation of blaNDM and altered bacterial metabolism. These findings suggest a potential trade-off between tigecycline resistance and CZA susceptibility that warrants further functional validation.