Meropenem is a clinically important antibacterial reserved for treatment of multi-resistant infections. In meropenem-resistant bacteria of the family Enterobacteriales, NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolysing meropenem with almost identical kinetics. We show that blaNDM-1 consistently confers meropenem resistance in wild-type Enterobacteriales, but blaIMP-1 does not. The reason is higher blaNDM-1 expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of blaNDM-1 positive Enterobacteriales because of amino acid starvation. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded blaNDM-1 having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same blaNDM-1 plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation, reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.

中文翻译：

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在临床环境中，肠道细菌清单表现出的金属-β-内酰胺酶的耐药性和适应性成本之间的权衡是对碳青霉烯耐药性的零星出现。

美罗培南是临床上重要的抗菌素，可用于治疗多重耐药性感染。在肠杆菌科的耐美罗培南的细菌中，尽管金属-β-内酰胺酶（MBL）水解美罗培南的动力学几乎相同，但NDM-1比IMP-1更为普遍。我们显示，blaNDM-1在野生型肠杆菌中始终赋予美罗培南耐药性，但blaIMP-1并非如此。原因是blaNDM-1表达较高，因为其启动子更强。然而，由于氨基酸饥饿，美洛培南抗性的成本降低了blaNDM-1阳性肠杆菌的适应性。同时，从临床病例中，我们鉴定出多个肠杆菌属。分离物携带带有修饰的启动子区的质粒编码的blaNDM-1。这种修饰将MBL的产量降低到与零适应性成本相关的水平，但因此，分离株不具有美罗培南抗性。但是，我们从携带相同blaNDM-1质粒的同一临床病例中鉴定出肺炎克雷伯菌。尽管由于ramR突变导致NDM-1产量低，但该分离物仍具有美罗培南抗药性，从而降低了包膜通透性。因此，总的来说，我们展示了如何解决MBL运输的阻力/适应性折衷。结果是在临床环境中偶发出现美罗培南耐药性。尽管由于ramR突变导致NDM-1产量较低，但该分离株仍具有美罗培南抗药性，从而降低了包膜通透性。因此，总的来说，我们展示了如何解决MBL运输的阻力/适应性折衷。结果是在临床环境中偶发出现美罗培南耐药性。尽管由于ramR突变导致NDM-1产量低，但该分离物仍具有美罗培南抗药性，从而降低了包膜通透性。因此，总的来说，我们展示了如何解决MBL运输的阻力/适应性折衷。结果是在临床环境中偶发出现美罗培南耐药性。