Sheng Huanjing, Huang Jinling, Han Zhaoyu, Liu Mi, Lü Zexun, Zhang Qian, Zhang Jinlei, Yang Jun, Cui Shenghui, Yang Baowei
College of Food Science and Engineering, Northwest A&F University, Xianyang, China.
School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
Front Microbiol. 2020 May 8;11:770. doi: 10.3389/fmicb.2020.00770. eCollection 2020.
The emergence of antibiotic-resistant through mutations led to mismatch repair (MMR) deficiency that represents a potential hazard to public health. Here, four representative MMR-deficient hypermutator strains and Typhimurium LT2 were used to comprehensively reveal the influence of MMR deficiency on antibiotic resistance among . Our results indicated that the mutation frequency ranged from 3.39 × 10 to 5.46 × 10 in the hypermutator. Mutation sites in MutS, MutL, MutT, and UvrD of the four hypermutators were all located in the essential and core functional regions. Mutation frequency of the hypermutator was most highly correlated with the extent of mutation in MutS. Mutations in MMR genes (S, T, L, and D) were correlated with increased mutation in antibiotic resistance genes, and the extent of antibiotic resistance was significantly correlated with the number of mutation sites in MutL and in ParC. The number of mutation sites in MMR genes and antibiotic resistance genes exhibited a significant positive correlation with the number of antibiotics resisted and with expression levels of S, T, and L. Compared to Typhimurium LT2, a total of 137 differentially expressed and 110 specifically expressed proteins were identified in the four hypermutators. Functional enrichment analysis indicated that the proteins significantly overexpressed in the hypermutators primarily associated with translation and stress response. Interaction network analysis revealed that the ribosome pathway might be a critical factor for high mutation frequency and multidrug resistance in MMR-deficient hypermutators. These results help elucidate the mutational dynamics that lead to hypermutation, antibiotic resistance, and activation of stress response pathways in .
通过突变产生的抗生素耐药性导致错配修复（MMR）缺陷，这对公众健康构成潜在危害。在此，使用四种具有代表性的MMR缺陷型高突变菌株和鼠伤寒沙门氏菌LT2，全面揭示MMR缺陷对沙门氏菌抗生素耐药性的影响。我们的结果表明，高突变菌株的突变频率范围为3.39×10至5.46×10。四种高突变菌株的MutS、MutL、MutT和UvrD中的突变位点均位于关键和核心功能区域。高突变菌株的突变频率与MutS中的突变程度相关性最高。MMR基因（S、T、L和D）中的突变与抗生素耐药基因的突变增加相关，抗生素耐药程度与MutL和ParC中的突变位点数量显著相关。MMR基因和抗生素耐药基因中的突变位点数量与耐药抗生素数量以及S、T和L的表达水平呈显著正相关。与鼠伤寒沙门氏菌LT2相比，在四种高突变菌株中总共鉴定出137种差异表达蛋白和110种特异性表达蛋白。功能富集分析表明，在高突变菌株中显著过表达的蛋白质主要与翻译和应激反应相关。相互作用网络分析表明，核糖体途径可能是MMR缺陷型高突变菌株中高突变频率和多药耐药性的关键因素。这些结果有助于阐明导致沙门氏菌高突变、抗生素耐药性和应激反应途径激活的突变动态。
