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Background <p>Multidrug-resistant <i>Klebsiella pneumoniae</i> poses a growing clinical challenge due to its ability to evade antibiotic treatment, particularly through the overexpression of efflux systems. Among these, the AcrAB-TolC pump is central to resistance against fluoroquinolones. While the global regulator’s MarA, SoxS, and Rob are known modulators of efflux in <i>Enterobacteriaceae</i>, their functional relevance in clinical <i>K</i>. <i>pneumoniae</i> remains insufficiently defined and largely correlation-based.</p> Objective <p>This study was designed to (1) determine the transcriptional association between the global regulators MarA, SoxS, and Rob with the AcrAB-TolC efflux system in multidrug-resistant (MDR) <i>Klebsiella pneumoniae</i>, and (2) functionally assess whether efflux contributes to fluoroquinolone resistance through PAβN-based inhibition assays. Together, these two analytical layers suggest a possible link between regulator expression and efflux-associated resistance reversal, without confirming direct regulatory activation.</p> Methods <p>Thirty clinical MDR isolates and ten susceptible controls were characterized via antibiotic susceptibility testing. Gene expression was quantified using qRT-PCR, normalized to 16S rRNA, and analyzed by the 2^–ΔΔCt method. Pearson correlation assessed relationships between gene expression and resistance. Phenotypic validation of efflux activity was performed using PAβN, an AcrAB-TolC inhibitor.</p> Results <p>MDR isolates exhibited significant overexpression of <i>marA</i> (5.0-fold), <i>soxS</i> (4.0-fold), <i>acrB</i> (7.9-fold), and other efflux components (<i>p</i> &lt; <i>0.001</i>). Strong positive correlations were observed between <i>marA/soxS</i> and <i>acrB</i> expression, suggesting a potential regulatory association. PAβN exposure reduced ciprofloxacin MICs by ≥ fourfold in 80% of high acrB expression isolates, supporting the involvement of active efflux mechanisms.</p> Conclusion <p>Our integrated findings indicate that higher <i>marA/soxS</i> expression is associated with increased gene expression of the AcrAB-TolC efflux pump and fluoroquinolone resistance in clinical MDR isolates, while PAβN-mediated efflux inhibition is associated with partial susceptibility restoration. Together, these results highlight global regulators and efflux pumps as actionable therapeutic targets for resistance reversal.</p>

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Integrated analysis of global regulators and efflux genes associated with antimicrobial resistance reversal in multidrug resistant Klebsiella pneumoniae

  • 期刊论文

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  • 发表日期：

    2026年2月5日

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  • Ali J. Obaid,
  • Ali J. Alkawaz,
  • Maryam S. Naser

摘要

Background

Multidrug-resistant Klebsiella pneumoniae poses a growing clinical challenge due to its ability to evade antibiotic treatment, particularly through the overexpression of efflux systems. Among these, the AcrAB-TolC pump is central to resistance against fluoroquinolones. While the global regulator’s MarA, SoxS, and Rob are known modulators of efflux in Enterobacteriaceae, their functional relevance in clinical K. pneumoniae remains insufficiently defined and largely correlation-based.

Objective

This study was designed to (1) determine the transcriptional association between the global regulators MarA, SoxS, and Rob with the AcrAB-TolC efflux system in multidrug-resistant (MDR) Klebsiella pneumoniae, and (2) functionally assess whether efflux contributes to fluoroquinolone resistance through PAβN-based inhibition assays. Together, these two analytical layers suggest a possible link between regulator expression and efflux-associated resistance reversal, without confirming direct regulatory activation.

Methods

Thirty clinical MDR isolates and ten susceptible controls were characterized via antibiotic susceptibility testing. Gene expression was quantified using qRT-PCR, normalized to 16S rRNA, and analyzed by the 2^–ΔΔCt method. Pearson correlation assessed relationships between gene expression and resistance. Phenotypic validation of efflux activity was performed using PAβN, an AcrAB-TolC inhibitor.

Results

MDR isolates exhibited significant overexpression of marA (5.0-fold), soxS (4.0-fold), acrB (7.9-fold), and other efflux components (p < 0.001). Strong positive correlations were observed between marA/soxS and acrB expression, suggesting a potential regulatory association. PAβN exposure reduced ciprofloxacin MICs by ≥ fourfold in 80% of high acrB expression isolates, supporting the involvement of active efflux mechanisms.

Conclusion

Our integrated findings indicate that higher marA/soxS expression is associated with increased gene expression of the AcrAB-TolC efflux pump and fluoroquinolone resistance in clinical MDR isolates, while PAβN-mediated efflux inhibition is associated with partial susceptibility restoration. Together, these results highlight global regulators and efflux pumps as actionable therapeutic targets for resistance reversal.