幽门螺杆菌多次治疗失败和多药耐药是棘手的临床问题。虽然我们创新推出大剂量甲硝唑补救方案能够根除大部分甲硝唑耐药菌株，然而公认的氧不敏感NADPH硝基还原酶（rdxA）突变（中止密码子等）与耐药水平（最低抑菌浓度MIC）和治疗成败无关，甲硝唑耐药机制一直未完全明确。我们初步研究发现，尽管都对甲硝唑高度耐药（高水平MIC），治疗成功组菌株的spoT表达水平、羟基自由基和转运蛋白HP0497低于治疗失败组，与rdxA中止密码子出现频率无关，推测严谨应答、氧应激和转运蛋白等在甲硝唑耐药治疗中起作用。本研究拟采集临床菌株、结合体内治疗结局和体外细菌干预实验，使用诱导耐药、耐药干预、生长曲线、定量PCR、基因敲除和再补足技术，确认spoT基因通过调控氧应激在甲硝唑耐药治疗中起作用。对甲硝唑耐药机理的研究有助于识别出不受大剂量甲硝唑方案影响的菌株，以避免不必要的药物干预和失败，为临床治疗提供依据。

It is difficult to treat the H pylori-positive patients with multiple resistant strains and multiple failures. Our recent studies found the regimens of high dosage of metronidazole achieved an excellent eradication rate even in metronidazole, clarithromycin and levofloxacin resistant strains. But the clinical outcomes have been not related to the well known oxygen-insensitive NAD(P)H nitroreductase mutation and high level minimal inhibitory concentration of metronidazole. The mechanism of H pylori to metronidazole resistance is unknown. Our primary data found that the expression of spoT in strains of success group and production of hydroxyl radicals (OH.) and tansportor HP0497 was significantly lower than those in failure group，but the prevalence of stop codon in rdxA was higher. Using standard strain 26695 and clinical isolates, bioinformatics, inducing resistance experiments, gene knockout and complementation, time-kill assay, growth curve are designed to investigate the stringent response activated on production of the alarmones guanosine pentaphosphate and guanosine tetraphosphate ((p)ppGpp), which are synthesized by the spoT gene products, oxidative stress-related genes and transporter HP0497 in metronidazole stress and treatment results. The purpose of this study is to elucidate the molecular mechanism of metronidazole resistance in H pylori and significantly applied some new policy to clinical treatment of H pylori infection.