Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene blaKPC.
Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene blaKPC.
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DOI：
10.1128/aac.00464-16
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发表时间：
2016-06
影响因子：
4.9
通讯作者：
Mathers AJ
中科院分区：
文献类型：
--
作者：
Sheppard AE;Stoesser N;Wilson DJ;Sebra R;Kasarskis A;Anson LW;Giess A;Pankhurst LJ;Vaughan A;Grim CJ;Cox HL;Yeh AJ;Modernising Medical Microbiology (MMM) Informatics Group;Sifri CD;Walker AS;Peto TE;Crook DW;Mathers AJ
最近在肠杆菌科中广泛出现的碳青霉烯类耐药性是一个主要的公共卫生问题，因为碳青霉烯类是治疗这一常见细菌病原体家族的最后手段。抗性基因可以通过不同的机制动员，包括接合和转座；然而，这种移动性在短期进化中的重要性尚不清楚，例如在医院内暴发疫情中。使用一家医院5年来281株blaKPC阳性肠杆菌科分离株的短读和长读全基因组测序相结合的方法，我们证明了这种碳青霉烯类耐药基因迅速传播到多个物种、菌株和质粒中。BlaKPC的迁移性发生在多个嵌套的遗传水平上，blaKPC菌株在个体之间传递，blaKPC质粒在菌株/物种之间频繁转移，blaKPC转座子Tn4401在质粒之间频繁转座。我们还发现Tn4401在不同的Tn2样元件中有一个共同的插入位点，这表明Tn4401在Tn2样元件之间的同源重组增强了Tn4401在不同质粒载体之间的传播。此外，虽然短读测序对于质粒组装有已知的局限性，但各种研究试图通过使用基于参考的方法来克服这一点。我们还证明，由于在这项研究中观察到的遗传迁移率，质粒结构可以是非常动态的，因此这些基于参考的方法以及传统的部分分型方法可能会产生非常误导的结论。总体而言，我们的发现表明，非克隆性耐药性基因的传播可以非常迅速，这对公共卫生监测和实现有效控制抗生素耐药性提出了重大挑战。
The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort against this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms, including conjugation and transposition; however, the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is unknown. Using a combination of short- and long-read whole-genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolates from a single hospital over 5 years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of blaKPC occurs at multiple nested genetic levels, with transmission of blaKPC strains between individuals, frequent transfer of blaKPC plasmids between strains/species, and frequent transposition of blaKPC transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this by the use of reference-based methods. We also demonstrate that, as a consequence of the genetic mobility observed in this study, plasmid structures can be extremely dynamic, and therefore these reference-based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that nonclonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance.