Inhibition of the Mycobacterium tuberculosis reserpine-sensitive efflux pump augments intracellular concentrations of ciprofloxacin and enhances susceptibility of some clinical isolates

详细信息    查看全文

• 作者：Tsi-Shu Huang ; Calvin M. Kunin ; Hui-Min Wang ; Bo-Shiun Yan ; Shiao-Ping Huang ; Yao-Shen Chen ; Susan Shin-Jung Lee ; Wan-Jr Syu
• 关键词：efflux ; fluoroquinolones ; Mycobacterium tuberculosis
• 刊名：Journal of the Formosan Medical Association
• 出版年：December, 2013
• 年：2013
• 卷：112
• 期：12
• 页码：789-794
• 全文大小：625 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencesml version="1.0" encoding="UTF-8"?>

Background/Purpose

Active efflux is known to play a major role in the resistance of many bacteria to antibiotics. To evaluate the possibility of overcoming resistance by suppressing the efflux, we determined the effect of reserpine, an efflux pump inhibitor.

Methods

Intracellular accumulations and the minimal inhibitory concentrations (MICs) of ciprofloxacin in m>M. tuberculosism> H37Rv and 16 clinical isolates were determined, compared, and analyzed. Nine of the clinical isolates were resistant to isoniazid and rifampin (multiple-drug resistant MDR). Five of these were resistant to ciprofloxacin.

Results

A reserpine-inhibited efflux system was identified in the H37Rv control and 10:1 (90.9%) of ciprofloxacin-susceptible and 4:1 (80%) of ciprofloxacin-resistant clinical isolates. The MIC of ciprofloxacin decreased in the presence of reserpine in 3/10 (30%) of the ciprofloxacin-susceptible and 2/4 (50%) of the MDR ciprofloxacin-resistant strains that expressed efflux pumps. Two of the efflux-positive, ciprofloxacin-resistant strains in which the MIC of ciprofloxacin was not decreased by reserpine were found to carry a D94A m>gyrAm> mutation. In contrast, two strains with the D94G m>gyrAm> mutation were susceptible to ciprofloxacin in the presence of reserpine. An efflux-negative strain, highly resistant to multiple antibiotics, was found to have a novel G247S mutation that differs from known mutations in the QRDR region of the m>gyrAm> gene.

Conclusion

These findings indicate t hat reserpine can increase intracellular concentrations of ciprofloxacin, but is unable to overcome other mechanisms of resistance in clinical isolates.