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<p>Probiotics present a promising preventive strategy for addressing urinary tract infections (UTIs) and serve as a viable alternative to conventional antimicrobial treatments. The integration of <i>Lactobacillus</i>-derived efflux pump inhibitors (EPIs) with conventional antibiotics presents a promising strategy to enhance the efficacy of treatments against antibiotic-resistant superbugs. In this study, we isolated eight vaginal <i>Lactobacillus</i> spp. from 54 healthy Indian women to explore their probiotic properties, specifically the ability of cell-free supernatant (CFS) from <i>Lactobacillus jensenii.</i> to inhibit efflux in Multi Drug Resistant (MDR) <i>E. coli</i> and <i>K. pneumoniae</i>. From the CFS, we obtained seven fractions, among which compound 7 (C7) markedly reduced the MIC of erythromycin against the <i>K. pneumoniae</i> MTCC 432 strain by 32-fold from 64 to 2&#xa0;µg and restored its sensitivity, indicating potent efflux inhibitory activity. Gas Chromatography-Mass Spectrometry (GC-MS) analysis identified one major compound from the C7 fraction as Cyclohexen-1-ol, 4-methyl-1-(1-methylethyl)-, (R)-, also known as (-)-Terpinen-4-ol. In vivo studies using zebrafish infected with clinical strain of <i>K. pneumoniae</i> 1845 followed by treatment with (-)-Terpinen-4-ol and erythromycin caused a significant 7-log reduction in bacterial bioburden. Additionally, time-kill assay demonstrated that the combination of erythromycin with (-)-Terpinen-4-ol caused a remarkable 7-log reduction in both <i>K. pneumoniae</i>, and <i>E. coli</i> cell counts. Furthermore, (-)-Terpinen-4-ol -erythromycin combination exhibited a six-log reduction in bacterial burden in infected T24 bladder cell lines and was found to be non-toxic. This study underscores the efflux inhibitory potential of (-)-Terpinen-4-ol extracted from the CFS of human vaginal probiotics, paving the way for future pharmacological research and therapeutic applications.</p>

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Human vaginal Lactobacillus Jensenii -derived (-)-Terpinen-4-ol restores antibiotic sensitivity by inhibiting efflux pumps in drug resistant E. coli and K. pneumoniae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月29日

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  • Veena G Nair,
  • Vineetha K Unnikrishnan,
  • Niraimathi Muralidharan,
  • Badri N S Venkatathri,
  • Rene Christena Lowrence,
  • Rajesh YBRD,
  • Dhiviya Narbhavi,
  • Anupriya A,
  • Prabhusaran N,
  • Saisubramanian Nagarajan

摘要

Probiotics present a promising preventive strategy for addressing urinary tract infections (UTIs) and serve as a viable alternative to conventional antimicrobial treatments. The integration of Lactobacillus-derived efflux pump inhibitors (EPIs) with conventional antibiotics presents a promising strategy to enhance the efficacy of treatments against antibiotic-resistant superbugs. In this study, we isolated eight vaginal Lactobacillus spp. from 54 healthy Indian women to explore their probiotic properties, specifically the ability of cell-free supernatant (CFS) from Lactobacillus jensenii. to inhibit efflux in Multi Drug Resistant (MDR) E. coli and K. pneumoniae. From the CFS, we obtained seven fractions, among which compound 7 (C7) markedly reduced the MIC of erythromycin against the K. pneumoniae MTCC 432 strain by 32-fold from 64 to 2 µg and restored its sensitivity, indicating potent efflux inhibitory activity. Gas Chromatography-Mass Spectrometry (GC-MS) analysis identified one major compound from the C7 fraction as Cyclohexen-1-ol, 4-methyl-1-(1-methylethyl)-, (R)-, also known as (-)-Terpinen-4-ol. In vivo studies using zebrafish infected with clinical strain of K. pneumoniae 1845 followed by treatment with (-)-Terpinen-4-ol and erythromycin caused a significant 7-log reduction in bacterial bioburden. Additionally, time-kill assay demonstrated that the combination of erythromycin with (-)-Terpinen-4-ol caused a remarkable 7-log reduction in both K. pneumoniae, and E. coli cell counts. Furthermore, (-)-Terpinen-4-ol -erythromycin combination exhibited a six-log reduction in bacterial burden in infected T24 bladder cell lines and was found to be non-toxic. This study underscores the efflux inhibitory potential of (-)-Terpinen-4-ol extracted from the CFS of human vaginal probiotics, paving the way for future pharmacological research and therapeutic applications.