Jeong J Y, Mukhopadhyay A K, Akada J K, Dailidiene D, Hoffman P S, Berg D E
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Bacteriol. 2001 Sep;183(17):5155-62. doi: 10.1128/JB.183.17.5155-5162.2001.
The relative importance of the frxA and rdxA nitroreductase genes of Helicobacter pylori in metronidazole (MTZ) susceptibility and resistance has been controversial. Jeong et al. (J. Bacteriol. 182:5082--5090, 2000) had interpreted that Mtz(s) H. pylori were of two types: type I, requiring only inactivation of rdxA to became resistant, and type II, requiring inactivation of both rdxA and frxA to become resistant; frxA inactivation by itself was not sufficient to confer resistance. In contrast, Kwon et al. (Antimicrob. Agents Chemother. 44:2133--2142, 2000) had interpreted that resistance resulted from inactivation either of frxA or rdxA. These two interpretations were tested here. Resistance was defined as efficient colony formation by single cells from diluted cultures rather than as growth responses of more dense inocula on MTZ-containing medium. Tests of three of Kwon's Mtz(s) strains showed that each was type II, requiring inactivation of both rdxA and frxA to become resistant. In additional tests, derivatives of frxA mutant strains recovered from MTZ-containing medium were found to contain new mutations in rdxA, and frxA inactivation slowed MTZ-induced killing of Mtz(s) strains. Northern blot analyses indicated that frxA mRNA, and perhaps also rdxA mRNA, were more abundant in type II than in type I strains. We conclude that development of MTZ resistance in H. pylori requires inactivation of rdxA alone or of both rdxA and frxA, depending on bacterial genotype, but rarely, if ever, inactivation of frxA alone, and that H. pylori strains differ in regulation of nitroreductase gene expression. We suggest that such regulatory differences may be significant functionally during human infection.
幽门螺杆菌的frxA和rdxA硝基还原酶基因在甲硝唑（MTZ）敏感性和耐药性方面的相对重要性一直存在争议。Jeong等人（《细菌学杂志》182:5082 - 5090，2000年）曾解释说，甲硝唑敏感（Mtz(s)）的幽门螺杆菌有两种类型：I型，仅需rdxA失活即可产生耐药性；II型，需rdxA和frxA均失活才会产生耐药性；单独的frxA失活不足以赋予耐药性。相比之下，Kwon等人（《抗菌药物与化疗》44:2133 - 2142，2000年）曾解释说，耐药性是由frxA或rdxA失活导致的。在此对这两种解释进行了验证。耐药性的定义是来自稀释培养物的单细胞能有效形成菌落，而非较密集接种物在含MTZ培养基上的生长反应。对Kwon的三个Mtz(s)菌株进行的测试表明，每个菌株都是II型，需rdxA和frxA均失活才会产生耐药性。在额外的测试中，从含MTZ培养基中回收的frxA突变菌株的衍生物被发现rdxA中有新突变，且frxA失活减缓了MTZ对Mtz(s)菌株的杀伤作用。Northern印迹分析表明，II型菌株中frxA mRNA以及可能的rdxA mRNA比I型菌株中的更丰富。我们得出结论，幽门螺杆菌中MTZ耐药性的产生取决于细菌基因型，单独rdxA失活或rdxA和frxA均失活均可导致耐药，但单独frxA失活导致耐药的情况极少（如果有的话），并且幽门螺杆菌菌株在硝基还原酶基因表达调控方面存在差异。我们认为，这种调控差异在人类感染过程中可能具有重要的功能意义。
