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Background <p>The global prevalence of multidrug-resistant bacteria has been rising at an alarming rate, posing a serious threat to both human and animal health. However, the mechanisms by which bacteria acquire antibiotic tolerance and subsequently develop resistance remain incompletely understood.</p> Methods <p>In this study, <i>Pasteurella multocida</i>, a common pathogen in the animal husbandry industry, was exposed to enrofloxacin, and genome resequencing, transcriptomic, and metabolomic analyses were performed to elucidate the adaptive mechanisms of <i>P. multocida</i> under fluoroquinolone-induced stress.</p> Results <p>Compared with the wild-type strain, the enrofloxacin-tolerant strain exhibited an extended lag phase, a prolonged logarithmic phase, reduced sensitivity to polymyxin B, reduced biofilm formation, and an elongated cellular morphology. Multi-omics analysis revealed a deletion in the <i>dusB</i> gene of the tolerant strain, resulting in a truncated non-functional protein. The deletion of <i>dusB</i> enhanced tolerance by prolonging the lag phase and reducing the growth rate. Moreover, the expression of genes in the CAMP pathway was up-regulated, and deletion of <i>cpxR</i> further promoted tolerance by modulating ribosome-associated genes. Integrated transcriptomic and metabolomic analyses indicated activation of the tricarboxylic acid (TCA) cycle during tolerance development.</p> Conclusion <p>This study identified <i>dusB</i> and <i>cpxR</i> as key genes mediating enrofloxacin tolerance in <i>P. multocida</i>, elucidated the association between the antibiotic tolerance, growth, and gene expression, and may provide potential targets for future strategies aimed at limiting tolerance-associated resistance development.</p>

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Integrated multi-omics analysis of fluoroquinolone tolerance mechanisms induced by enrofloxacin in Pasteurella multocida

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Yu Qi,
  • Jiayi Li,
  • Muhammad Inam,
  • Xinyu Li,
  • Ling-Cong Kong,
  • Hong-Xia Ma

摘要

Background

The global prevalence of multidrug-resistant bacteria has been rising at an alarming rate, posing a serious threat to both human and animal health. However, the mechanisms by which bacteria acquire antibiotic tolerance and subsequently develop resistance remain incompletely understood.

Methods

In this study, Pasteurella multocida, a common pathogen in the animal husbandry industry, was exposed to enrofloxacin, and genome resequencing, transcriptomic, and metabolomic analyses were performed to elucidate the adaptive mechanisms of P. multocida under fluoroquinolone-induced stress.

Results

Compared with the wild-type strain, the enrofloxacin-tolerant strain exhibited an extended lag phase, a prolonged logarithmic phase, reduced sensitivity to polymyxin B, reduced biofilm formation, and an elongated cellular morphology. Multi-omics analysis revealed a deletion in the dusB gene of the tolerant strain, resulting in a truncated non-functional protein. The deletion of dusB enhanced tolerance by prolonging the lag phase and reducing the growth rate. Moreover, the expression of genes in the CAMP pathway was up-regulated, and deletion of cpxR further promoted tolerance by modulating ribosome-associated genes. Integrated transcriptomic and metabolomic analyses indicated activation of the tricarboxylic acid (TCA) cycle during tolerance development.

Conclusion

This study identified dusB and cpxR as key genes mediating enrofloxacin tolerance in P. multocida, elucidated the association between the antibiotic tolerance, growth, and gene expression, and may provide potential targets for future strategies aimed at limiting tolerance-associated resistance development.