Integrated Analysis of Global Regulators and Efflux Genes in MDR Klebsiella pneumoniae:Unlocking Targets for Antimicrobial Reversal
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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. Objective: This study aimed to elucidate the transcriptional dynamics between global regulators (marA, soxS, rob) and efflux pump components (acrA, acrB, tolC) in multidrug-resistant K. pneumoniae and to validate the functional role of efflux in fluoroquinolone resistance. 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 emerged between marA/soxS and acrB expression, implicating coordinated regulatory control. PAβN exposure reduced ciprofloxacin MICs by ≥ 4-fold in 80% of high-acrB isolates, confirming active efflux involvement. Conclusion: The data establish MarA and SoxS as principal activators of the AcrAB-TolC efflux system in clinical MDR K. pneumonia , driving fluoroquinolone resistance. Rob showed minimal impact. Functional inhibition of efflux restored anti-biotic susceptibility in most isolates, highlighting global regulators and efflux pumps as promising targets for adjunctive therapy to combat resistance.
