Smith M A, Edwards D I
Chemotherapy Research Unit, University of East London, UK.
J Antimicrob Chemother. 1995 Sep;36(3):453-61. doi: 10.1093/jac/36.3.453.
Resistance of Helicobacter pylori to metronidazole during therapy for gastroduodenal ulcers is claimed to be responsible for failure to eradicate the pathogen and thus the disease. Resistance to metronidazole and other nitroimidazoles is rare and documented only for anaerobes; the mechanism of resistance in typical microaerophiles, like Helicobacter, is not known. We have studied metronidazole uptake using high performance liquid chromatography in metronidazole sensitive and resistant strains of H. pylori under conditions of microaerophilia and in anaerobiosis. The uptake of metronidazole was faster in sensitive strains than resistant ones and was also increased in anaerobiosis. Drug uptake and the rate of cell kill was found to be dependent upon the relative oxygen tension of the environment and the cell density, both of which determine the redox conditions of the media. We suggest that resistance displayed in microaerophilia, but which disappears in anaerobiosis, may not involve futile cycling nor the induction of superoxide dismutase and catalase. We further propose that resistant organisms may have alterations in the pattern of pyruvate metabolism as documented for anaerobic bacteria and protozoa and that resistance in microaerophilia may involve the relative efficiencies of detoxifying oxygen in susceptible and resistant strains of H. pylori.
在胃十二指肠溃疡治疗期间，幽门螺杆菌对甲硝唑产生耐药性被认为是导致无法根除该病原体进而引发疾病的原因。对甲硝唑和其他硝基咪唑类药物的耐药性很罕见，且仅在厌氧菌中有记载；像幽门螺杆菌这样典型的微需氧菌的耐药机制尚不清楚。我们使用高效液相色谱法，在微需氧和厌氧条件下，对甲硝唑敏感和耐药的幽门螺杆菌菌株进行了甲硝唑摄取的研究。敏感菌株中甲硝唑的摄取速度比耐药菌株快，且在厌氧条件下摄取量也会增加。发现药物摄取和细胞杀灭率取决于环境的相对氧张力和细胞密度，这两者都决定了培养基的氧化还原条件。我们认为，在微需氧条件下表现出的耐药性，但在厌氧条件下消失，可能既不涉及无效循环，也不涉及超氧化物歧化酶和过氧化氢酶的诱导。我们进一步提出，耐药菌可能像厌氧菌和原生动物那样，丙酮酸代谢模式发生了改变，并且微需氧条件下的耐药性可能涉及幽门螺杆菌敏感菌株和耐药菌株中氧气解毒效率的差异。
