Choudhuri B S, Sen S, Chakrabarti P
Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Calcutta, 700 009, India.
Biochem Biophys Res Commun. 1999 Mar 24;256(3):682-4. doi: 10.1006/bbrc.1999.0357.
Resistance to isoniazid (INH), a frontline, antituberculosis drug, presents a major problem in the chemotherapy of tuberculosis. Although several targets of INH have been identified, the mechanism of INH resistance remains incompletely understood. This report demonstrates that INH accumulation in Mycobacterium smegmatis is enhanced both upon addition of both a proton motive force (pmf) uncoupler, carbonylcyanide m-chlorophenylhydrazone (CCCP), and upon addition of ortho-vanadate, an inhibitor of ATP-dependent efflux pumps. Both the Deltapsi and DeltapH components of the pmf are likely to be involved as judged by the effects of valinomycin and nigericin, respectively. Reserpine, an inhibitor of the human MDR1 P-glycoprotein, enhances INH accumulation in a manner similar to o-vanadate. Verapamil, a calcium channel blocker, also enhances INH uptake. Taken together, the results provide evidence of the involvement of both pmf- and ATP-dependent extrusion systems in INH efflux in M. smegmatis, making it important to evaluate the role of such systems in INH resistance in pathogenic mycobacteria.
对一线抗结核药物异烟肼（INH）产生耐药性是结核病化疗中的一个主要问题。尽管已经确定了INH的几个作用靶点，但对INH耐药机制仍未完全了解。本报告表明，在耻垢分枝杆菌中，添加质子动力势（pmf）解偶联剂羰基氰化物间氯苯腙（CCCP）以及添加ATP依赖性外排泵抑制剂原钒酸盐后，INH的积累均会增强。分别根据缬氨霉素和尼日利亚菌素的作用判断，pmf的ΔΨ和ΔpH成分可能均参与其中。利血平是人类MDR1 P-糖蛋白的抑制剂，其增强INH积累的方式与原钒酸盐类似。钙通道阻滞剂维拉帕米也能增强INH的摄取。综上所述，这些结果提供了证据，表明pmf依赖性和ATP依赖性外排系统均参与耻垢分枝杆菌中INH的外排，因此评估此类系统在致病性分枝杆菌对INH耐药中的作用很重要。
