幽门螺杆菌IS605介导rdxA突变导致甲硝唑耐药性的作用机制研究

幽门螺杆菌感染可导致胃炎、消化道溃疡、胃癌等多种疾病，其耐药率不断上升导致根除率下降和公共卫生安全风险。幽门螺杆菌甲硝唑耐药率在我国和全球均处于较高水平，且耐药机制复杂多样。文献报道临床分离的幽门螺杆菌甲硝唑耐药菌株中存在pIS605插入突变rdxA的现象，可能是一种新的基于插入序列转座的耐药突变机制。我们的前期研究证实了，在甲硝唑作用下，pIS605可插入突变rdxA使菌株产生耐药性；pIS605也可插入破坏pyrF以响应5-FOA筛选；且不同菌株中转座活性存在差异。我们认为这是菌株应对选择压力的一种机制，甲硝唑选择下这种插入突变发生的机制、菌株间差异和应答调控过程等尚不清楚。本研究拟通过对IS605转座酶介导pIS605转座的机制、不同菌株中转座活性差异和甲硝唑作用下相关调控因子进行研究，阐明IS605介导rdxA突变的作用机制，为幽门螺杆菌甲硝唑耐药性的产生和散播提供新的研究思路。

Helicobacter pylori infection can lead to a variety of diseases, such as gastritis, peptic ulcers and gastric adenocarcinoma. The efficacy of the H. pylori eradication treatment has decreased dramatically because of antibiotic resistance. Drug-resistant infections already cost too many lives today, and it will get worse in the future if we do not act now. Resistance of H. pylori to metronidazole has reached considerably high levels in China and overseas. The mechanism of metronidazole resistance for H. pylori is comlpex and varies from strain to strain. It has been reported that insertions of a partial insertion sequence IS605 (pIS605) into rdxA causing metronidazole resistance were identified in H. pylori clinical isolates, which may be a novel IS-mediated mutation mechanism of metronidazole resistance. In our preliminary study, we provided experimental evidence that pIS605 could insert into rdxA under metronidazole selection. Also, pIS605 could insert into pyrF under 5-FOA counterselection. Furthermore, the transposition action of pIS605 varied between H. pylori ATCC 43504 and 26695 strains. We inferred that this IS-mediated mutation mechanism was one of the responses of H. pylori to the selective pressure. Several key points about this process need to be elucidated: how the insertion happens, why the transposition varies between strains, and which genes participate in the response to metronidazole selection and the regulation of IS605. We propose to study the transposition mechanism of pIS605 mediated by IS605 transposases, the reason why pIS605 transposition varies between strains and identify genes regulating the transposition process under metronidazole selection. Elucidation of the mechanism of IS605-mediated mutation of rdxA will provide a new viewpoint for the study of the occurrence and spread of metronidazole resistance in H. pylori.